Activators of class I histone deacetlyases (HDACs) and uses thereof

ABSTRACT

The present invention provides compounds of Formulae (A), (B), (C), and (D), pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, pharmaceutical compositions thereof, and kits thereof. The present invention further provides methods of using the compounds to treat or prevent neurological disorders, including Alzheimer&#39;s disease, Parkinson&#39;s disease, Huntington&#39;s disease, ALS (amyotrophic lateral sclerosis), traumatic brain injury, ischemic brain injury, stroke, frontal temporal dementia, Pick&#39;s disease, corticobasal degeneration, supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinal cerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xeroderma pigmentosaum, and Bloom syndrome. In one aspect, the methods include administering to a subject in need of treatment for a neurological disorder a therapeutically effective amount of DAC-001, DAC-002, DAC-003, DAC-009, or DAC-012, or a compound of Formula (A), (B), (C), or (D).

RELATED APPLICATIONS

The present application is a division of and claims priority under 35U.S.C. § 120 to U.S. patent application, U.S. Ser. No. 13/554,670, filedJul. 20, 2012, which claims priority under 35 U.S.C. § 119(e) to U.S.provisional application, U.S. Ser. No. 61/510,885, filed Jul. 22, 2011,each of which is incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with Government support under grant numberRC1-AG035711 awarded by the National Institutes of Health. TheGovernment has certain rights in the invention.

FIELD OF THE INVENTION

The field of the invention pertains to activators of class I histonedeacetylases and their uses in the treatment of neurological disorders.

BACKGROUND OF THE INVENTION

In a variety of neurodegenerative disorders such as ischemia andAlzheimer's disease (Hayashi et al., Neuropathol. Appl. Neurobiol.(2000) 26:390-97; Rashidian et al., Biochim. Biophys. Acta. (2007)1772:484-93; Vincent et al., J. Cell. Biol. (1996) 132:413-25.; Yang etal., J. Neurosci. (2001) 21:2661-68), neurons engage in aberrant cellcycle activities, expressing cell cycle markers such as Ki-67 and PCNA,and undergoing a limited extent of DNA replication (Yang et al., J.Neurosci. (2001) 21:2661-68). This behavior is remarkable consideringthat neurons have terminally differentiated during development andremain quiescent for decades prior to the onset of these events. Whilethe underlying mechanisms are poorly understood, multiple lines ofevidence suggest that these activities play an early and contributoryrole in neuronal death (Andorfer et al., J. Neurosci. (2005) 25:5446-54;Busser et al., J. Neurosci. (1998) 18:2801-07; Herrup et al.,Development. (1995) 121:2385-95; Nguyen et al., Cell Death Differ.(2002) 9:1294-306.). For example, overexpression of cell cycleactivity-inducing proteins such as SV40 large T antigen, c-myc, c-Myb,or E2F-1 causes neuronal death in vitro and in vivo (al-Ubaidi et al.,Proc. Natl. Acad. Sci. USA (1992) 89:1194-98.; Konishi et al., J.Neurosci. (2003) 23:1649-58; Liu et al., Neuron. (2001) 32:425-38;McShea et al., Biochim. Biophys. Acta. (2007) 1772:467-72), whilepharmacological inhibitors of CDKs or other cell cycle components canexert neuroprotective effects (Padmanabhan et al., J. Neurosci. (1999)19:8747-56).

DNA damage may also be involved in multiple conditions involvingneuronal death (Adamec et al., Brain Res. (1999) 849:67-77; Ferrante etal., J. Neurochem. (1997) 69:2064-74; Hayashi et al., Brain Res. (1999)832:159-63; Kruman et al., Neuron. (2004) 41:549-61; Robison et al., J.Neurol. Sci. (1984) 64:11-20). For example, oxidative damage to neuronalDNA has been observed in rodent models of ischemia (Hayashi et al.,Brain Res. (1999) 832:159-63). Accumulation of reactive oxygen speciesresults in DNA damage, cell cycle activity, and neurodegeneration inmutant mice with disrupted apoptosis-inducing factor (AIF) (Klein etal., Nature (2002) 419:367-74). In addition, congenital syndromes withDNA repair gene mutations, such as ataxia telangiectasia and Werner'ssyndrome, display a progressive neurodegeneration phenotype,demonstrating the importance of maintaining DNA integrity in the adultbrain (Rolig et al., Trends Neurosci. (2000) 23:417-24). Importantly,DNA damage is involved in the aging of the human brain (Lu et al.,Nature (2004) 429:883-91), which suggests that DNA damage may play arole in age-dependent neurological disorders as well.

Nucleosomes, the primary scaffold of chromatin folding, are dynamicmacromolecular structures, influencing the conformation of chromatin insolution. The nucleosome core is made up of the histone proteins, H2A,H2B, H3 and H4. Histone acetylation causes nucleosomes and nucleosomalarrangements to behave with altered biophysical properties. The balancebetween the activities of histone acetyl transferases (HAT) and histonedeacetylases (HDAC) determines the level of histone acetylation.Acetylated histones cause relaxation of chromatin and activation of genetranscription, whereas deacetylated chromatin generally istranscriptionally inactive.

HDACs have been grouped in four classes depending on sequence identity,domain organization, and function: Class I: HDAC1 (histone deacetylase1), HDAC2, HDAC3, HDAC8; Class II: HDAC4, HDAC5, HDAC6, HDAC7, HDAC9,HDAC10; Class III: SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7; andClass IV: HDAC11. Within Class I, HDAC1, HDAC2 and HDAC8 are primarilyfound in the nucleus while HDAC3 and Class II HDACs can shuttle betweenthe nucleus and the cytoplasm. Class III HDACs (the sirtuins), couplethe removal of the acetyl group of the histone to NAD hydrolysis,thereby coupling the deacetylation reaction to the energy status of thecell.

A need remains for new compounds and treatment options that result inthe protection of cells, including neuronal cells to DNA damage. Thesuppression of DNA damage in neuronal cells is an important mechanismfor suppressing neuronal cell death and provides an opportunity for thetreatment or prevention of various neurological disorders.

SUMMARY OF THE INVENTION

The present invention provides inventive compounds of the Formulae (A),(B), (C), and (D), pharmaceutically acceptable salts, solvates,hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled derivatives, and prodrugs thereof, pharmaceuticalcompositions thereof, and kits thereof. The present invention furtherprovides methods of using the inventive compounds, pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, co-crystals,tautomers, stereoisomers, isotopically labeled derivatives, and prodrugsthereof, pharmaceutical compositions thereof, and kits thereof, to studyactivation of class I histone deacetylase (HDAC) and as therapeutics,e.g., for the treatment of neurological disorders, such as Alzheimer'sdisease, Parkinson's disease, Huntington's disease, ALS (amyotrophiclateral sclerosis), traumatic brain injury, ischemic brain injury,stroke, frontal temporal dementia, Pick's disease, corticobasaldegeneration, supra cerebral palsy, prion diseases (e.g.,Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome,Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinalcerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia,hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xerodermapigmentosaum, and Bloom syndrome.

In one aspect, the invention provides compounds of Formula (A):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein

each instance of X^(A1), X^(A2), and X^(A3) is independently oxygen orsulfur;

each instance of R^(A1) and R^(A2) is independently hydrogen, a nitrogenprotecting group, or C₁₋₆ alkyl;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

each instance of R^(A3) and R^(A4) is independently selected from thegroup consisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A3a),—N(R^(A3b))₂, —SR^(A3a), —C(═O)R^(A3a), —C(═O)OR^(A3a), —C(═O)SR^(A3a),—C(═O)N(R^(A3b))₂, —OC(═O)R^(A3a), —OC(═O)OR^(A3a), —OC(═O)SR^(A3a),—OC(═O)N(R^(A3b))₂, —NR^(A3b)C(═O)R^(A3b), —NR^(A3b)C(═O)OR^(A3a),—NR^(A3b)C(═O)SR^(A3a), —NR^(A3b)C(═O)N(R^(A3b))₂, —SC(═O)R^(A3a),—SC(═O)OR^(A3a), —SC(═O)SR^(A3a), —SC(═O)N(R^(A3b))₂,—C(═NR^(A3b))R^(A3a), —C(═NR^(A3b))OR^(A3a), —C(═NR^(A3b))SR^(A3a),—C(═NR^(A3b))N(R^(A3b))₂, —OC(═NR^(A3b))R^(A3a), —OC(═NR^(A3b))OR^(A3a),—OC(═NR^(A3b))SR^(A3a), —O(═NR^(A3b))N(R^(A3b))₂,—NR^(A3b)C(═NR^(A3b))R^(A3b), —NR^(A3b)C(═NR^(A3b))OR^(A3a),—NR^(A3b)C(═NR^(A3b))SR^(A3a), —NR^(A3b)C(═NR^(A3b))N(R^(A3b))₂,—SC(═NR^(A3b))R^(A3a), —SC(═NR^(A3b))OR^(A3a), —SC(═NR^(A3b))SR^(A3a),—SC(═NR^(A3b))N(R^(A3b))₂, —C(═S)R^(A3a), —C(═S)OR^(A3a),—C(═S)SR^(A3a), —C(═S)N(R^(A3b))₂, —OC(═S)R^(A3a), —OC(═S)OR^(A3a),—OC(═S)SR^(A3a), —OC(═S)N(R^(A3b))₂, —NR^(A3b)C(═S)R^(A3b),—NR^(A3b)C(═S)OR^(A3a), —NR^(A3b)C(═S)SR^(A3a),—NR^(A3b)C(═S)N(R^(A3b))₂, —SC(═S)R^(A3a), —SC(═S)OR^(A3a),—SC(═S)SR^(A3a), —SC(═S)N(R^(A3b))₂, —S(═O)R^(A3a), —SO₂R^(A3a),—NR^(A3b)SO₂R^(A3a), —SO₂N(R^(A3b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(A3a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(A3b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(A3b)groups are joined to form an optionally substituted heterocyclic ring;

m is 0, 1, 2, 3, or 4; and

n is 0, 1, 2, or 3.

In another aspect, the invention provides compounds of Formula (B):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein

each instance of X^(B1), X^(B3), and X^(B4) is independently oxygen,sulfur, NR^(B4a), or C(R^(B4b))₂, wherein R^(B4a) is hydrogen, anitrogen protecting group, or C₁₋₆ alkyl, and each occurrence of R^(B4b)is hydrogen, halogen, or C₁₋₆ alkyl, or two R^(B4b) groups are joined toform an optionally substituted carbocyclic or heterocyclic ring;

X^(B2) is nitrogen or CR^(B2a), wherein R^(B2a) is hydrogen, halogen, orC₁₋₆ alkyl;

each instance of R^(B1) is independently selected from the groupconsisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(B1a),—N(R^(B1b))₂, —SR^(B1a), —C(═O)R^(B1a), —C(═O)OR^(B1a), —C(═O)SR^(B1a),—C(═O)N(R^(B1b))₂, —OC(═O)R^(B1a), —OC(═O)OR^(B1a), —OC(═O)SR^(B1a),—OC(═O)N(R^(B1b))₂, —NR^(B1b)C(═O)R^(B1b), —NR^(B1b)C(═O)OR^(B1a),—NR^(B1b)C(═O)SR^(B1a), —NR^(B1b)C(═O)N(R^(B1b))₂, —SC(═O)R^(B1a),—SC(═O)OR^(B1a), —SC(═O)SR^(B1a), —SC(═O)N(R^(B1b))₂,—NR^(B1b)C(═O)N(R^(B1b))₂, —SC(═O)R^(B1A), —SC(═O)OR^(B1a),—SC(═O)SR^(B1a), —SC(═O)N(R^(B1b))₂, —C(═NR^(B1b))R^(B1a),—C(═NR^(B1b))OR^(B1a), —C(═NR^(B1b))SR^(B1a), —(═NR^(B1b))N(R^(B1b))₂,—OC(═NR^(B1b))R^(B1a), —OC(═NR^(B1b))OR^(B1a), —OC(═NR^(B1b))SR^(B1a),—OC(═NR^(B1b))N(R^(B1b))₂, —NR^(B1b)C(═NR^(B1b))R^(B1b),—NR^(B1b)C(═NR^(B1b))OR^(B1a), —NR^(B1b)C(═NR^(B1b))SR^(B1a),—NR^(B1b)C(═NR^(B1b))N(R^(B1b))₂, —SC(═NR^(B1b))R^(B1a),—SC(═NR^(B1b))OR^(B1a), —SC(═NR^(B1b))SR^(B1a),—SC(═NR^(B1b))NR^(B1b))₂, —C(═S)R^(B1a), —C(═S)OR^(B1a), —C(═S)SR^(B1a),—C(═S)N(R^(B1b))₂, —OC(═S)R^(B1a), —OC(═S)OR^(B1a), —OC(═S)SR^(B1a),—OC(═S)N(R^(B1b))₂, —NR^(B1b)C(═S)R^(B1b), —NR^(B1b)C(═S)OR^(B1a),—NR^(B1b)C(═S)SR^(B1a), —NR^(B1b)C(═S)N(R^(B1b))₂, —SC(═S)R^(B1a),—SC(═S)OR^(B1a), —SC(═S)SR^(B1a), —SC(═S)N(R^(B1b))₂, —S(═O)R^(B1a),—SO₂R^(B1a), —NR^(B1b)SO₂R^(B1a), —SO₂N(R^(B1b))₂, —CN, —SCN, and —NO₂,wherein each occurrence of R^(B1a) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl, and each occurrence of R^(B1b) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or a nitrogen protecting group, ortwo R^(B1b) groups are joined to form an optionally substitutedheterocyclic ring;

each instance of R^(B2), R^(B3), R^(B4), and R^(B5) is independentlyhydrogen, halogen, or C₁₋₆ alkyl;

R^(B6) is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(B6a), —N(R^(B6b))₂, or—SR^(B6a), wherein each occurrence of R^(B6a) is independently hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl, and each occurrence of R^(B6b) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or a nitrogen protecting group, ortwo R^(B6b) groups are joined to form an optionally substitutedheterocyclic ring;

p is 0, 1, 2, 3, or 4.

In yet another aspect, the invention provides compounds of Formula (C):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein

X^(C1) is oxygen, sulfur, or NR^(C1a), wherein R^(C1a) is hydrogen, anitrogen protecting group, or C₁₋₆ alkyl;

each instance of X^(C2), X^(C3), and X^(C4) is independently nitrogen orCR^(C4a), wherein R^(C4a) is hydrogen, halogen, or C₁₋₆ alkyl;

L is a bond; cyclic or acyclic, substituted or unsubstituted alkylene;cyclic or acyclic, substituted or unsubstituted alkenylene; cyclic oracyclic, substituted or unsubstituted alkynylene; cyclic or acyclic,substituted or unsubstituted heteroalkylene; cyclic or acyclic,substituted or unsubstituted heteroalkenylene; cyclic or acyclic,substituted or unsubstituted heteroalkynylene; substituted orunsubstituted arylene; or substituted or unsubstituted heteroarylene;

each instance of R^(C1) and R^(C2) is independently selected from thegroup consisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(C2a),—N(R^(C2b))₂, —SR^(C2a), —(═O)R^(C2a), —C(═O)OR^(C2a), —C(═O)SR^(C2a),—C(═O)N(R^(C2b))₂, —OC(═O)R^(C2a), —OC(═O)OR^(C2a), —OC(═O)SR^(C2a),—OC(═O)N(R^(C2b))₂, —NR^(C2b)C(═O)R^(C2b), —NR^(C2b)C(═O)OR^(C2a),—NR^(C2b)C(═O)SR^(C2a), —NR^(C2b)C(═O)N(R^(C2b))₂, —SC(═O)R^(C2a),—SC(═O)OR^(C2a), —SC(═O)SR^(C2a), —SC(═O)N(R^(C2b))₂,—C(═NR^(C2b))R^(C2a), —C(═NR^(C2b))OR^(C2a), —C(═NR^(C2b))SR^(C2a),—C(═NR^(C2b))N(R^(C2b))₂, —OC(═NR^(C2b))R^(C2a), —OC(═NR^(C2b))OR^(C2a),—OC(═NR^(C2b))SR^(C2a), —OC(═NR^(C2b))N(R^(C2b))₂,—NR^(C2b)C(═NR^(C2b))R^(C2b), —NR^(C2b)C(═NR^(C2b))OR^(C2a),—NR^(C2b)C(═NR^(C2b))SR^(C2a), —NR^(C2b)C(═NR^(C2b))N(R^(C2b))₂,—SC(═NR^(C2b))R^(C2a), —SC(═NR^(C2b))OR^(C2a), —SC(═NR^(C2b))SR^(C2a),—SC(═NR^(C2b))N(R^(C2b))₂, —C(═S)R^(C2a), —C(═S)OR^(C2a),—C(═S)SR^(C2a), —C(═S)N(R^(C2b))₂, —OC(═S)R^(C2a), —OC(═S)OR^(C2a),—OC(═S)SR^(C2a), —OC(═S)N(R^(C2b))₂, —NR^(C2b)C(═S)R^(C2b),—NR^(C2b)C(═S)OR^(C2a), —NR^(C2b)C(═S)SR^(C2a),—NR^(C2b)C(═S)N(R^(C2b))₂, —SC(═S)R^(C2a), —SC(═S) OR^(C2a),—SC(═S)SR^(C2a), —SC(═S)N(R^(C2b))₂, —S(═O)R^(C2a), —SO₂R^(C2a),—NR^(C2b)SO₂R^(C2a), —SO₂N(R^(C2b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(C2a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(C2b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(C2b)groups are joined to form an optionally substituted heterocyclic ring;

q is 0, 1, 2, 3, or 4; and

r is 0, 1, 2, 3, 4, or 5.

In yet another aspect, the invention provides compounds of Formula (D):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein

each instance of X^(D1) is independently oxygen, sulfur, NR^(D1a), orC(R^(D1b))₂, wherein R^(D1a) is hydrogen or C₁₋₆ alkyl, and eachoccurrence of R^(D1b) is hydrogen, halogen, or C₁₋₆ alkyl, or twoR^(D1b) groups are joined to form an optionally substituted carbocyclicor heterocyclic ring;

s is 0, 1, 2, 3, 4, 5, or 6;

each instance of R^(D1) and R^(D2) is independently hydrogen, an oxygenprotecting group, C₁₋₆ alkyl, —C(═O)R^(D2a), —C(═O)OR^(D2a),—C(═O)SR^(D2a), —C(═O)N(R^(D2b))₂, —S(═O)R^(D2a), or —S(═O)₂R^(D2a),wherein each occurrence of R^(D2a) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl, and each occurrence of R^(D2b) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or a nitrogen protecting group, ortwo R^(D2b) groups are joined to form an optionally substitutedheterocyclic ring;

each instance of R^(D3) and R^(D4) is independently selected from thegroup consisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(D4a),—N(R^(D4b))₂, —SR^(D4a), —C(═O)R^(D4a), —C(═O)OR^(D4a), —C(═O)SR^(D4a),—C(═O)N(R^(D4b))₂, —OC(═O)R^(D4a), —OC(═O)OR^(D4a), —OC(═O)SR^(D4a),—OC(═O)N(R^(D4b))₂, —NR^(D4b)C(═O)R^(D4b), —NR^(D4b)C(═O)OR^(D4a),—NR^(D4b)C(═O)SR^(D4a), —NR^(D4b)C(═O)N(R^(D4b))₂, —SC(═O)R^(D4a),—SC(═O)OR^(D4a), —SC(═O)SR^(D4a), —SC(═O)N(R^(D4b))₂,—C(═NR^(D4b))R^(D4a), —C(═NR^(D4b))OR^(D4a), —C(═NR^(D4b))SR^(D4a),—C(═NR^(D4b))N(R^(D4b))₂, —OC(═NR^(D4b))R^(D4a), —OC(═NR^(D4b))OR^(D4a),—OC(═NR^(D4b))SR^(D4a), —OC(═NR^(D4b))N(R^(D4b))₂,—NR^(D4b)C(═NR^(D4b))R^(D4b), —NR^(D4b)C(═NR^(D4b))OR^(D4a),—NR^(D4b)C(═NR^(D4b))SR^(D4a), —NR^(D4b)C(═NR^(D4b))N(R^(D4b))₂,—SC(═NR^(D4b))R^(D4a), —SC(═NR^(D4b))OR^(D4a), —SC(═NR^(D4b))SR^(D4a),—SC(═NR^(D4b))N(R^(D4b))₂, —C(═S)R^(D4a), —C(═S)OR^(D4a),—C(═S)SR^(D4a), —C(═S)N(R^(D4b))₂, —OC(═S)R^(D4a), —OC(═S)OR^(D4a),—OC(═S)SR^(D4a), —OC(═S)N(R^(D4b))₂, —NR^(D4b)C(═S)R^(D4b),—NR^(D4b)C(═S)OR^(D4a), —NR^(D4b)C(═S)SR^(D4a),—NR^(D4b)C(═S)N(R^(D4b))₂, —SC(═S)R^(D4a), —SC(═S)OR^(D4a),—SC(═S)SR^(D4a), —SC(═S)N(R^(D4b))₂, —S(═O)R^(D4a), —SO₂R^(D4a),—NR^(D4b)SO₂R^(D4a), —SO₂N(R^(D4b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(D4a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(D4b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(D4b)groups are joined to form an optionally substituted heterocyclic ring;

t is 0, 1, 2, or 3; and

u is 0, 1, 2, 3, 4 or 5.

In still another aspect, provided are pharmaceutical compositionscomprising a compound of any of the Formulae (A), (B), (C), and (D), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, and optionally a pharmaceutically acceptableexcipient.

In still another aspect, the invention provides methods and compositionsfor the suppression of DNA damage in neuronal cells.

In still another aspect, the invention provides methods and compositionsfor the treatment of neurological disorders. In certain embodiments, themethod comprises administering to a subject in need of treatment for aneurological disorder a therapeutically effective amount of a class IHDAC (histone deacetylase) activator to treat the neurological disorder.In some embodiments, the neurological disorder is Alzheimer's disease,Parkinson's disease, Huntington's disease, ALS (Amyotrophic lateralsclerosis), traumatic brain injury, or ischemic brain injury. In someembodiments, the class I HDAC activator is selected from the group ofcompounds consisting of:

and compounds of the Formulae (A), (B), (C), and (D), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, or pharmaceutical compositions thereof.

In another aspect, the invention provides kits for treating aneurological disorder comprising a first container comprising a class IHDAC activator selected from the group of compounds consisting ofDAC-001, DAC-002, DAC-003, DAC-009, DAC-012, and compounds of theFormulae (A), (B), (C), and (D), and pharmaceutically acceptable salts,solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled derivatives, and prodrugs thereof, orpharmaceutical compositions thereof.

This Application refers to various issued patent, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference.

Each of the limitations of the invention can encompass variousembodiments of the invention. It is, therefore, anticipated that each ofthe limitations of the invention involving any one element orcombinations of elements can be included in each aspect of theinvention. This invention is not limited in its application to thedetails of construction and the arrangement of components set forth inthe following description or illustrated in the drawings. The inventionis capable of other embodiments and of being practiced or of beingcarried out in various ways. Also, the phraseology and terminology usedherein is for the purpose of description and should not be regarded aslimiting. The use of the terms “including”, “comprising”, “having”,“containing”, “involving”, and variations thereof herein is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGrawHill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, IN 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), n-propyl(C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl(C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈)and the like. Unless otherwise specified, each instance of an alkylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a “substituted alkyl”) with oneor more substituents. In certain embodiments, the alkyl group isunsubstituted C₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, thealkyl group is substituted C₁₋₁₀ alkyl.

“Perhaloalkyl” is a substituted alkyl group as defined herein whereinall of the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. In some embodiments, the alkyl moietyhas 1 to 8 carbon atoms (“C₁₋₈ perhaloalkyl”). In some embodiments, thealkyl moiety has 1 to 6 carbon atoms (“C₁₋₆ perhaloalkyl”). In someembodiments, the alkyl moiety has 1 to 4 carbon atoms (“C₁₋₄perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 3 carbonatoms (“C₁₋₃ perhaloalkyl”). In some embodiments, the alkyl moiety has 1to 2 carbon atoms (“C₁₋₂ perhaloalkyl”). In some embodiments, all of thehydrogen atoms are replaced with fluoro. In some embodiments, all of thehydrogen atoms are replaced with chloro. Examples of perhaloalkyl groupsinclude CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

The term “heteroalkyl,” as used herein, refers to an alkyl moiety, asdefined herein, which contains one or more oxygen, sulfur, nitrogen,phosphorus, or silicon atoms, e.g., in place of carbon atoms.

The term “heteroalkenyl,” as used herein, refers to an alkenyl moiety,as defined herein, which contains one or more oxygen, sulfur, nitrogen,phosphorus, or silicon atoms, e.g., in place of carbon atoms.

The term “heteroalkynyl,” as used herein, refers to an alkynyl moiety,as defined herein, which contains one or more oxygen, sulfur, nitrogen,phosphorus, or silicon atoms, e.g., in place of carbon atoms.

“Carbocyclyl” or “carbocyclic” refers to a radical of a nonaromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo(2.2.1)heptanyl (C₇),bicyclo(2.2.2)octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro(4.5)decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3 to10-membered non aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10-memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10-memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10-membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10-membered nonaromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen, sulfur,boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8-membered nonaromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8-membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6-membered nonaromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6-membered heterocyclyl”). In someembodiments, the 5-6-membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the5-6-membered heterocyclyl has 1-2 ring heteroatoms selected fromnitrogen, oxygen, and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has one ring heteroatom selected from nitrogen, oxygen, andsulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiorenyl.Exemplary 4-membered heterocyclyl groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an alkyl group substituted with an optionally substituted aryl group.

“Heteroaryl” refers to a radical of a 5-10-membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10-membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl hasone ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl, and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an alkyl group substituted with an optionally substitutedheteroaryl group.

“Partially unsaturated” refers to a group that includes at least onedouble or triple bond. The term “partially unsaturated” is intended toencompass rings having multiple sites of unsaturation, but is notintended to include aromatic groups (e.g., aryl or heteroaryl groups) asherein defined. Likewise, “saturated” refers to a group that does notcontain a double or triple bond, i.e., the group contains all singlebonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, which are divalent bridging groups arefurther referred to using the suffix ene, e.g., alkylene, alkenylene,alkynylene, carbocyclylene, heteroalkylene, heteroalkenylene,heteroalkynylene, heterocyclylene, arylene, and heteroarylene.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl, or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that result in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂R^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃,—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa),—P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂,—OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14-membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(RN, —NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee),—SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OS 0₂R^(ee), —S(═O)R^(ee),—Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee),—C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂,—OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or twogeminal R^(dd) substituents can be joined to form ═0 or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of e is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃, —C(═S)N(C₁₋₆ alkyl), C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,C(═O)S(C₁₋₆ alkyl), C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl), —OP(═O)(OC₁₋₆ alkyl)₂,C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

A “leaving group” is an art-understood term referring to a molecularfragment that departs with a pair of electrons in heterolytic bondcleavage, wherein the molecular fragment is an anion or neutralmolecule. See, for example, Smith, March's Advanced Organic Chemistry6th ed. (501-502). Exemplary leaving groups include, but are not limitedto, halogen (e.g., chloro, bromo, iodo), activated hydroxyl groups(e.g., —OC(═O)SR^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂,—OS(═O)R^(aa), —OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂ wherein R^(aa), R^(bb), and R^(cc) are as definedherein), substituted thiol groups (e.g., —SR^(aa), for example, as amolecular fragment departing from of a compound of the formulaR^(aa)S—SR^(aa)), substituted nitrogen groups (e.g., —NR^(bb), forexample, as a molecular fragment departing from of a compound of formulaBr—N(R^(bb))₂, Cl—N(R^(bb))₂, I—N(R^(bb))₂ ^(b), and F—N(R^(bb))₂), —CN,and —N₂.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substitutents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Amide nitrogen protecting groups (e.g., —C(═O)R^(aa)) include, but arenot limited to, formamide, acetamide, chloroacetamide,trichloroacetamide, trifluoroacetamide, phenylacetamide,3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide,N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide,o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide,(N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide,3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Carbamate nitrogen protecting groups (e.g., —C(═O)OR^(aa)) include, butare not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-(9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl))methylcarbamate (DBDTmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DBtBOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, pbromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, (2-(1,3-dithianyl))methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Sulfonamide nitrogen protecting groups (e.g., —S(═O)₂R^(aa)) include,but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide,2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl (10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-(2-(trimethylsilyl)ethoxy)methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-((4-methoxyphenyl)diphenylmethyl)amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-((2-pyridyl)mesityl)methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-(phenyl(pentaacylchromium- or tungsten)acyl)amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (pAOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-((2-chloro-4-methyl)phenyl)-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec),2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate,alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenylcarbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate,alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate,alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxylnapththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, andP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

An “isomer” includes any and all geometric isomers and stereoisomers.For example, “isomers” include cis and transisomers, E- and Z-isomers,R- and S-enantiomers, diastereomers, (D)isomers, (L)-isomers, racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention.

“Tautomer” includes two or more interconvertable compounds resultingfrom at least one formal migration of a hydrogen atom and at least onechange in valency (e.g., a single bond to a double bond, a triple bondto a double bond, or vice versa). The exact ratio of the tautomersdepends on several factors, including temperature, solvent, and pH.Tautomerizations (i.e., the reaction providing a tautomeric pair) may becatalyzed by acid or base. Exemplary tautomerizations includeketo-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; andenamine-to-(a different) enamine tautomerizations.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

The term “animal,” as used herein, refers to humans as well as non-humananimals, including, e.g., mammals, birds, reptiles, amphibians, andfish. Preferably, the non-human animal is a mammal (e.g., a rodent, amouse, a rat, a rabbit, a monkey, a dog, a cat, a primate, or a pig). Anon-human animal may be a transgenic animal.

“Salt” or “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid,or with organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid, or malonic acid, or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate,laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium, and N⁺(Cl⁻ ₄alkyl)₄ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, quaternarysalts.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middleaged adult or senior adult)) and/or othernonhuman animals, for example mammals (e.g., primates (e.g., cynomolgusmonkeys, rhesus monkeys); commercially relevant mammals such as cattle,pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g.,commercially relevant birds such as chickens, ducks, geese, and/orturkeys), reptiles, amphibians, and fish. In certain embodiments, thenonhuman animal is a mammal. The nonhuman animal may be a male or femaleand at any stage of development. A nonhuman animal may be a transgenicanimal.

“Treat,” “treating,” and “treatment” contemplate an action that occurswhile a subject is suffering from a condition which reduces the severityof the condition or retards or slows the progression of the condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the condition and which inhibitsor reduces the severity of the condition (“prophylactic treatment”).

An “effective amount” of a compound refers to an amount sufficient toelicit the desired biological response, i.e., treating the condition. Aswill be appreciated by those of ordinary skill in this art, theeffective amount of a compound of the invention may vary depending onsuch factors as the desired biological endpoint, the pharmacokinetics ofthe compound, the condition being treated, the mode of administration,and the age and health of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

A “therapeutically effective amount” of a compound is an amountsufficient to provide a therapeutic benefit in the treatment of acondition or to delay or minimize one or more symptoms associated withthe condition. A therapeutically effective amount of a compound means anamount of a therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of the condition, or enhances the therapeutic efficacy of anothertherapeutic agent.

A “prophylactically effective amount” of a compound is an amountsufficient to prevent a condition, or one or more symptoms associatedwith the condition or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of a therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the condition. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

A “pharmaceutically acceptable excipient” is an excipient that isnon-toxic to recipients at the dosages and concentrations employed, andis compatible with other ingredients of the formulation.Pharmaceutically acceptable excipients include any and all solvents,diluents, or other liquid vehicles, dispersions, suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants, and the like, assuited to the particular dosage form desired. General considerations informulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21st Edition(Lippincott Williams & Wilkins, 2005).

A “small molecule” is a low molecular weight organic compound which isnot a polymer. The term small molecule, especially within the field ofpharmacology, is usually restricted to a molecule that also binds withhigh affinity to a biopolymer such as protein, polysaccharide, ornucleic acid and in addition alters the activity or function of thebiopolymer. The upper limit for a small molecule's molecular weight isabout 800 Daltons which allows for the possibility to rapidly diffuseacross cell membranes so that they can reach intracellular sites ofaction.

A “protein” or “peptide” comprises a polymer of amino acid residueslinked together by peptide bonds. The term, as used herein, refers toproteins, polypeptides, and peptide of any size, structure, or function.Typically, a protein will be at least three amino acids long. A proteinmay refer to an individual protein or a collection of proteins.Inventive proteins preferably contain only natural amino acids, althoughnon-natural amino acids (i.e., compounds that do not occur in nature butthat can be incorporated into a polypeptide chain) and/or amino acidanalogs as are known in the art may alternatively be employed. Also, oneor more of the amino acids in an inventive protein may be modified, forexample, by the addition of a chemical entity such as a carbohydrategroup, a hydroxyl group, a phosphate group, a farnesyl group, anisofarnesyl group, a fatty acid group, a linker for conjugation,functionalization, or other modification, etc. A protein may also be asingle molecule or may be a multi-molecular complex. A protein may bejust a fragment of a naturally occurring protein or peptide. A proteinmay be naturally occurring, recombinant, or synthetic, or anycombination of these.

“Histones” are highly alkaline proteins found in eukaryotic cell nucleithat package and order the DNA into structural units called nucleosomes.They are the chief protein components of chromatin, acting as spoolsaround which DNA winds, and play a role in gene regulation.

“Histone deacetylases” (HDACs) are a class of enzymes that remove acetylgroups from an ε-N-acetyl lysine amino acid on a histone. DNA is wrappedaround histones, and DNA expression is regulated by acetylation anddeacetylation.

“Class I histone deacetylase” or “class I HDAC” is a subclass of HDACs.

“HDAC1” or “histone deacetylase 1” is a subclass of class I HDACs.

A “DAC” refers to a compound that activates class I HDACs' enzymaticfunction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an overview of small molecule modulators of class I HDACsand relevance to response to DNA damage, DNA repair, andneuroprotection. HDAC1, HDAC2, HDAC3, and HDAC8 are zinc-dependenthydrolases that remove acetyl groups from the ε-amino group of lysineside chains. Class I HDACs have also been found to have other enzymaticactivities, including esterase activity.

FIGS. 2A to 2B show HDAC1 microfluidics. FIG. 2A shows an assay controldata of 7,080 negative control samples (DMSO). FIG. 2B shows 580ginkgetin positive controls (50 μM).

FIGS. 3A to 3B show HDAC1 microfluidics high-throughput screening data.FIG. 3A depicts a primary microfluidic fluorescence reader trace forginkgetin (positive control; for its structure, see FIG. 6A) showingincreased conversion of the peptidic substrate FAM-TSRHKacKL to thedeacetylated product FAM-TSRHKKL (illustrated with arrows). FIG. 3Bdepicts a primary microfluidic fluorescence reader trace for DAC-001,showing increased conversion of the peptidic substrate FAM-TSRHKacKL tothe deacetylated product FAM-TSRHKKL (illustrated with arrows).

FIG. 4 shows that DAC compounds reduce histone acetylation. DACcompounds were added to HEK293T cells for 20 h. Vehicle was DMSO.Histones were acid-extracted and analyzed by Western blot for Ac-H3K56,Ac-H4K12, Ac-H3K14 and Ac-H2B. Histone 3 was used as the loadingcontrol.

FIGS. 5A to 5C show that DAC compounds protect cells from stress-inducedcell death. FIG. 5A shows that DAC compounds protect cells againstoxidative stress. 10 μM DAC-003 can significantly protect cells fromoxidative insults (*p<0.05, compound versus vehicle treatment, student'st-test). FIG. 5B shows that DAC compounds protect cells from DNAdamage-induced stress. Cells were treated with etoposide, atopoisomerase II inhibitor, to generate DNA double strand breaks (DSB).It was found that DAC-001, DAC-002, DAC-003, DAC-009, and DAC-012significantly protect cells from DSB-induced cell death (***p<0.001,compound versus vehicle treatment, student's t-test). FIG. 5C shows thatDAC compounds have minimal effects on cell proliferation and survival attheir working concentration (5 μM for DAC-001 and DAC-003; 10 μM for theothers).

FIGS. 6A to 6C show the twenty-one (21) hit structures from the highthroughput HDAC1 activator screen.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention provides compounds that activate Class I histonedeacetlyases (HDACs), and pharmaceutical compositions thereof, for thetreatment of human disease. The present invention further providesmethods of using the compounds described herein, e.g., as biologicalprobes to study the activation of HDACs, and as therapeutics, e.g., inthe treatment of neurological disorders, such as Alzheimer's disease,Parkinson's disease, Huntington's disease, ALS (Amyotrophic lateralsclerosis), traumatic brain injury, ischemic brain injury, stroke,frontal temporal dementia, Pick's disease, corticobasal degeneration,supra cerebral palsy, prion diseases (e.g., Creutzfeldt-Jakob disease,Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, andKuru), Nieman Pick type C, spinal cerebellar ataxia, spinal musculardystrophy, ataxia telangiectasia, hippocampal sclerosis, Cockaynesyndrome, Werner syndrome, xeroderma pigmentosaum, or Bloom syndrome.

Compounds

47,144 compounds were screened for hit compounds, which enhance theenzymatic activity of class I HDAC, especially, HDAC1. Of the hitcompounds, multiple common structural frameworks were identified,suggesting the existence of a defined structure-activity-relationshipfor HDAC1 activation.

The compounds depicted below and herein may be prepared by conventionalchemical transformations (including protecting group methodologies),e.g., those described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley and Sons(1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof. The compounds can also besynthesized in manners similar to those described with necessarymodifications as recognized by those skilled in the art.

In one aspect, provided is a compound of Formula (A):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein

each instance of X^(A1), X^(A2), and X^(A3) is independently oxygen orsulfur;

each instance of R^(A1) and R^(A2) is independently hydrogen, a nitrogenprotecting group, or C₁₋₆ alkyl;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

each instance of R^(A3) and R^(A4) is independently selected from thegroup consisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A3a),—N(R^(A3b))₂, —SR^(A3a), —C(═O)R^(A3a), —C(═O)OR^(A3a), —C(═O)SR^(A3a),—C(═O)N(R^(A3b))₂, —OC(═O)R^(A3a), —OC(═O)OR^(A3a), —OC(═O)SR^(A3a),—OC(═O)N(R^(A3b))₂, —NR^(A3b)C(═O)R^(A3b), —NR^(A3b)C(═O)OR^(A3a),—NR^(A3b)C(═O)SR^(A3a), —NR^(A3b)C(═O)N(R^(A3b))₂, —SC(═O)R^(A3a),—SC(═O)OR^(A3a), —SC(═O)SR^(A3a), —SC(═O)N(R^(A3b))₂,—C(═NR^(A3b))R^(A3a), —C(═NR^(A3b))OR^(A3a), —C(═NR^(A3b))SR^(A3a),—C(═NR^(A3b))N(R^(A3b))₂, —OC(═NR^(A3b))R^(A3a), —OC(═NR^(A3b))OR^(A3a),—OC(═NR^(A3b))SR^(A3a), —OC(═NR^(A3b))N(R^(A3b))₂,—NR^(A3b)C(═NR^(A3b))R^(A3b), —NR^(A3b)C(═NR^(A3b))OR^(A3a),—NR^(A3b)C(═NR^(A3b))SR^(A3a), —NR^(A3b)C(═NR^(A3b))N(R^(A3b))₂,—SC(═NR^(A3b))R^(A3a), —SC(═NR^(A3b))OR^(A3a), —SC(═NR^(A3b))SR^(A3a),—SC(═NR^(A3b))N(R^(A3b))₂, —C(═S)R^(A3a), —C(═S)OR^(A3a),—C(═S)SR^(A3a), —C(═S)N(R^(A3b))₂, —OC(═S)R^(A3a), —OC(═S)OR^(A3a),—OC(═S)SR^(A3a), —OC(═S)N(R^(A3b))₂, —NR^(A3b)C(═S)R^(A3b),—NR^(A3b)C(═S)OR^(A3a), —NR^(A3b)C(═S)SR^(A3a),—NR^(A3b)C(═S)N(R^(A3b))₂, —SC(═S)R^(A3a), —SC(═S)OR^(A3a),—SC(═S)SR^(A3a), —SC(═S)N(R^(A3b))₂, —S(═O)R^(A3a), —SO₂R^(A3a),—NR^(A3b)SO₂R^(A3a), —SO₂NR^(A3b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(A3a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(A3b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(A3b)groups are joined to form an optionally substituted heterocyclic ring;

m is 0, 1, 2, 3, or 4; and

n is 0, 1, 2, or 3.

In certain embodiments, X^(A1), X^(A2), and X^(A3) are oxygen. Incertain embodiments, X^(A1) and X^(A2) are oxygen, and X^(A3) is sulfur.In certain embodiments, X^(A1) and X^(A3) are oxygen, and X^(A2) issulfur. In certain embodiments, X^(A2) and X^(A3) are oxygen, and X^(A1)is sulfur. In certain embodiments, X^(A1) and X^(A2) are sulfur, andX^(A3) is oxygen. In certain embodiments, X^(A1) and X^(A3) are sulfur,and X^(A2) is oxygen. In certain embodiments, X^(A2) and X^(A3) aresulfur, and X^(A1) is oxygen. In certain embodiments, X^(A1), X^(A2),and X^(A3) are sulfur.

In certain embodiments, R^(A1) is hydrogen. In certain embodiments,R^(A1) is a nitrogen protecting group. In certain embodiments, R^(A1) isC₁₋₆ alkyl. In certain embodiments, R^(A1) is methyl.

In certain embodiments, R^(A2) is hydrogen. In certain embodiments,R^(A2) is a nitrogen protecting group. In certain embodiments, R^(A2) isC₁₋₆ alkyl. In certain embodiments, R^(A2) is methyl.

In certain embodiments, R^(A1) and R^(A2) are both hydrogen.

In certain embodiments, X^(A1) and X^(A3) are oxygen, X^(A2) is sulfur,and R^(A1) and R^(A2) are hydrogen.

In certain embodiments, Ar is aryl. In certain embodiments, Ar issubstituted aryl.

In certain embodiments, Ar is heteroaryl. In certain embodiments, Ar issubstituted heteroaryl.

In certain embodiments, each instance of R^(A3) is independentlyoptionally substituted alkyl. In certain embodiments, each instance ofR^(A3) is independently optionally substituted C₁₋₆ alkyl. In certainembodiments, each instance of R^(A3) is independently optionallysubstituted methyl. In certain embodiments, each instance of R^(A3) isindependently methyl.

In certain embodiments, each instance of R^(A4) is independentlyoptionally substituted alkyl. In certain embodiments, each instance ofR^(A4) is independently optionally substituted C₁₋₆ alkyl. In certainembodiments, each instance of R^(A4) is independently optionallysubstituted methyl. In certain embodiments, each instance of R^(A4) isindependently optionally substituted hydroxyl-substituted alkyl. Incertain embodiments, each instance of R^(A4) is independently optionallysubstituted hydroxyl-substituted C₁₋₆ alkyl. In certain embodiments,each instance of R^(A4) is independently substituted hydroxymethyl. Incertain embodiments, each instance of R^(A4) is independentlyhydroxymethyl.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, m is 2. In certain embodiments, m is 3. In certainembodiments, m is 4.

In certain embodiments, X^(A1) and X^(A3) are oxygen, X^(A2) is sulfur,R^(A1) and R^(A2) are hydrogen, and m is 0.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3.

In certain embodiments, wherein Ar is optionally substituted phenyl,provided is a compound of Formula (A-I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein

X^(A1), X^(A2), X^(A3), R^(A1), R^(A2), R^(A3), R^(A4), m, and n are asdefined herein;

each instance of R^(A1) is independently selected from the groupconsisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(A1a),—N(R^(A1b))₂, —SR^(A1a), —C(═O)R^(A1a), —C(═O)OR^(A1a), —C(═O)SR^(A1a),—C(═O)N(R^(A1b))₂, —OC(═O)R^(A1a), —OC(═O)OR^(A1), —OC(═O)SR^(A1a),—OC(═O)N(R^(A1b))₂, —NR^(A1b)C(═O)R^(A1b), —NR^(A1b)C(═O)OR^(A1a),—NR^(A1b)C(═O)SR^(A1a), —NR^(A1b)C(═O)N(R^(A1b))₂, —SC(═O)R^(A1a),—SC(═O)OR^(A1a), —SC(═O)SR^(A1a), —SC(═O)N(R^(A1b))₂,—C(═NR^(A1b))R^(A1a), —C(═NR^(A1b))OR^(A1a), —C(═NR^(A1b))SR^(A1a),—C(═NR^(A1b))N(R^(A1b))₂, —OC(═NR^(A1b))R^(A1a), —OC(═NR^(A1b))OR^(A1a),—OC(═NR^(A1b))SR^(A1b), —OC(═NR^(A1b))N(R^(A1b))₂,—NR^(A1b)C(═NR^(A1b))R^(A1b), —NR^(A1b)C(═NR^(A1b))OR^(A1a),—NR^(A1b)C(═NR^(A1b))SR^(A1a), —NR^(A1b)C(═NR^(A1b))N(R^(A1b))₂,—SC(═NR^(A1b))R^(A1a), —SC(═NR^(A1b))OR^(A1a), —SC(═NR^(A1b))SR^(A1a),—SC(═NR^(A1b))N(R^(A1b))₂, —C(═S)R^(A1a), —C(═S)OR^(A1a),—C(═S)SR^(A1a), —C(═S)N(R^(A1b))₂, —OC(═S)R^(A1a), —OC(═S)OR^(A1a),—OC(═S)SR^(A1a), —OC(═S)N(R^(A1b))₂, —NR^(A1b)C(═S)R^(A1b),—NR^(A1b)C(═S)OR^(A1a), —NR^(A1b)C(═S)SR^(A1a),—NR^(A1b)C(═S)N(R^(A1b))₂, —SC(═S)R^(A1a), —SC(═S)OR^(A1a),—SC(═S)SR^(A1a), —SC(═S)NR^(A1b))₂, —S(═O)R^(A1a), —SO₂R^(A1a),—NR^(A1b)SO₂R^(A1a), —SO₂NR^(A1b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(Ala) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, or eachoccurrence of R^(A1b) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, or anitrogen protecting group, or two R^(A1b) groups are joined to form aheterocyclic ring; and

j is 0, 1, 2, 3, 4, or 5.

In certain embodiments of Formula (A-I), j is 0. In certain embodiments,j is 1. In certain embodiments, j is 2. In certain embodiments, j is 3.In certain embodiments, j is 4. In certain embodiments, j is 5.

In certain embodiments, provided is a compound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(A1), X^(A2), X^(A3), R^(A1), R^(A2),R^(A4), R^(A1), m, and n are as defined herein.

In certain embodiments, provided is a compound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein wherein R^(A3), R^(A4), R^(A1), m, and nare as defined herein.

In certain embodiments, R^(A1) is C₁₋₆ alkyl. In certain embodiments,R^(A1) is methyl. In certain embodiments, R^(A1) is ethyl. In certainembodiments, R^(A1) is propyl. In certain embodiments, R^(A1) is butyl.

In certain embodiments, provided is a compound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(A1), X^(A2), X^(A3), Ar, R^(A1),R^(A2), and R^(A4) are as defined herein.

In certain embodiments, provided is a compound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(A1), X^(A2), X^(A3), Ar, R^(A1),R^(A2), and R^(A3) are as defined herein.

In certain embodiments, wherein Ar is a optionally substitutedthiophenyl, provided is a compound of Formula (A-VI):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein

X^(A1), X^(A2), X^(A3), R^(A1), R^(A2), R^(A3), R^(A4), m and n are asdefined herein;

each instance of R^(A11) is independently selected from the groupconsisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(AIIa),—N(R^(AIIb))₂, —SR^(AIIa), —C(═O)R^(AIIa), —C(═O)OR^(AIIa),—C(═O)SR^(AIIa), —C(═O)N(R^(AIIb))₂, —OC(═O)R^(AIIa), —OC(═O)OR^(AIIa),—OC(═O)SR^(AIIa), —OC(═O)N(R^(AIIb))₂, —NR^(AIIb)C(═O)R^(AIIb),—NR^(AIIb)C(═O)OR^(AIIa), —NR^(AIIb)C(═O)SR^(AIIa),—NR^(AIIb)C(═O)N(R^(AIIb))₂, —SC(═O)R^(AIIa), —SC(═O)OR^(AIIa),—SC(═O)SR^(AIIa), —SC(═O)N(R^(AIIb))₂, —C(═NR^(AIIb))R^(AIIa),—C(═NR^(AIIb))OR^(AIIa), —C(═NR^(AIIb))SR^(AIIa),—C(═NR^(AIIb))N(R^(AIIb))₂, —OC(═NR^(AIIb))R^(AIIa),—OC(═NR^(AIIb))OR^(AIIa), —OC(═NR^(AIIb))SR^(AIIa),—OC(═NR^(AIIb))N(R^(AIIb))₂, —NR^(AIIb)C(═NR^(AIIb),—NR^(AIIb)C(═NR^(AIIb))OR^(AIIa), —NR^(AIIb)C(═NR^(AIIb))SR^(AIIa),—NR^(AIIb)C(═NR^(AIIb))N(R^(AIIb))₂, —SC(═NR^(AIIb))R^(AIIa),—SC(═NR^(AIIb))OR^(AIIa), —SC(═NR^(AIIb))SR^(AIIa),—SC(═NR^(AIIb))N(R^(AIIb))₂, —C(═S)R^(AIIa), —C(═S)OR^(AIIa),—C(═S)SR^(AIIa), —C(═S)N(R^(AIIb))₂, —OC(═S)R^(AIIa), —OC(═S)OR^(AIIa),—OC(═S)SR^(AIIa), —OC(═S)N(R^(AIIb))₂, —NR^(AIIb)C(═S)R^(AIIb),—NR^(AIIb)C(═S)OR^(AIIa), —NR^(AIIb)C(═S)SR^(AIIa),—NR^(AIIb)C(═S)N(R^(AIIb))₂, —SC(═S)R^(AIIa), —SC(═S)OR^(AIIa),—SC(═S)SR^(AIIa), —SC(═S)N(R^(AIIb))₂, —S(═O)R^(AIIa), —SO₂R^(AIIa),—NR^(AIIb)SO₂R^(AIIa), —SO₂N(R^(AIIb))₂, —CN, —SCN, and —NO₂, whereineach occurrence of R^(AIIa) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, and each occurrence of R^(AIIb) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or a nitrogen protecting group, ortwo R^(AIIb) groups are joined to form a heterocyclic ring; and

k is 0, 1, 2, or 3.

In certain embodiments of Formula (A-VI), k is 0. In certainembodiments, k is 1.

In certain embodiments, k is 2. In certain embodiments, k is 3.

In certain embodiments of Formula (A-VI), wherein k is 1, provided is acompound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(A1), X^(A2), X^(A3), R^(A1), R^(A2),R^(A3), R^(A4), R^(A11), m,

and n are as defined herein.

In certain embodiments of Formula (A-VI), wherein n is 1, provided is acompound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(A1), X^(A2), X^(A3), R^(A1), R^(A2),R^(A3), R^(A4), k, and m are as defined herein.

In certain embodiments of Formula (A-VI), provided is a compound of anyof the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(A1), X^(A2), X^(A3), R^(A1), R^(A2),R^(A3), R¹¹, k, and m, are as defined herein.

In certain embodiments, provided is a compound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(A3), R^(A11), k, and m are as definedherein.

In a certain embodiment, the compound of Formula (A) is not of theformula:

or a pharmaceutically acceptable salt thereof.

Another hit from the library was identified with a structural frameworkas shown in Formula (B):

Therefore, in certain embodiments, provided is a compound of Formula(B), and pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, and prodrugs thereof, wherein each instance of X^(B1),X^(B3), and X^(B4) is independently oxygen, sulfur, NR^(B4a), orC(R^(B4b))₂, wherein R^(B4a) is hydrogen, a nitrogen protecting group,or C₁₋₆ alkyl, and each occurrence of R^(B4b) is hydrogen, halogen, orC₁₋₆ alkyl, or two R^(B4b) groups are joined to form an optionallysubstituted carbocyclic or heterocyclic ring;

X^(B2) is nitrogen or CR^(B2a), wherein R^(B2a) is hydrogen, halogen, orC₁₋₆ alkyl;

each instance of R^(B1) is independently selected from the groupconsisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(B1a),—N(R^(B1b))₂, —SR^(B1a), —C(═O)R^(B1a), —C(═O)OR^(B1a), —C(═O)SR^(B1a),—C(═O)N(R^(B1b))₂, —OC(═O)R^(B1a), —OC(═O)OR^(B1a), —OC(═O)SR^(B1a),—OC(═O)N(R^(B1b))₂, —NR^(B1b)C(═O)R^(B1b), —NR^(B1b)C(═O)OR^(B1a),—NR^(B1b)C(═O)SR^(B1a), —NR^(B1b)C(═O)N(R^(B1b))₂, —SC(═O)R^(B1a),—SC(═O)OR^(B1a), —SC(═O)SR^(B1a), —SC(═O)N(R^(B1b))₂,—C(═NR^(B1b))R^(B1a), —C(═NR^(B1b))OR^(B1a), —C(═NR^(B1b))SR^(B1a),—C(═NR^(B1b))N(R^(B1b))₂, —OC(═NR^(B1b))R^(B1a), —OC(═NR^(B1b))OR^(B1a),—OC(═NR^(B1b))SR^(B1a), —OC(═NR^(B1b))N(R^(B1b))₂,—NR^(B1b)C(═NR^(B1b))R^(B1b), —NR^(B1b)C(═NR^(B1b))OR^(B1a),—NR^(B1b)C(═NR^(B1b))SR^(B1a), —NR^(B1b)C(═NR^(B1b))N(R^(B1b))₂,—SC(═NR^(B1b))R^(B1a), —SC(═NR^(B1b))OR^(B1a), —SC(═NR^(B1b))SR^(B1a),—SC(═NR^(B1b))NR^(B1b))₂, —C(═S)R^(B1a), —C(═S)OR^(B1a), —C(═S)SR^(B1a),—C(═S)N(R^(B1b))₂, —OC(═S)R^(B1a), —OC(═S)OR^(B1a), —OC(═S)SR^(B1a),—OC(═S)N(R^(B1b))₂, —NR^(B1b)C(═S)R^(B1b), —NR^(B1b)C(═S)OR^(B1a),—NR^(B1b)C(═S)SR^(B1a), —NR^(B1b)C(═S)N(R^(B1b))₂, —SC(═S)R^(B1a),—SC(═S)OR^(B1a), —SC(═S)SR^(B1a), —SC(═S)N(R^(B1b))₂, —S(═O)R^(B1a),—SO₂R^(B1a), —NR^(B1b)SO₂R^(B1a), —SO₂N(R^(B1b))₂, —CN, —SCN, and —NO₂,wherein each occurrence of R^(B1a) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl, and each occurrence of R^(B1b) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or a nitrogen protecting group, ortwo R^(B1b) groups are joined to form an optionally substitutedheterocyclic ring;

each instance of R^(B2), R^(B3), R^(B4), and R^(B5) is independentlyhydrogen, halogen, or C₁₋₆ alkyl;

R^(B6) is hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(B6a), —N(R^(B6b))₂, or—SR^(B6a), wherein each occurrence of R^(B6a) is independently hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl, and each occurrence of R^(B6b) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or a nitrogen protecting group, ortwo R^(B6b) groups are joined to form an optionally substitutedheterocyclic ring;

p is 0, 1, 2, 3, or 4.

In certain embodiments, X^(B1) is oxygen. In certain embodiments, X^(B1)is sulfur. In certain embodiments, X^(B1) is NR^(B4a), wherein NR^(B4a)is as defined herein. In certain embodiments, X^(B1) is NH. In certainembodiments, X^(B1) is C(R^(B4b))₂, wherein R^(B4b) is defined herein.

In certain embodiments, X^(B2) is nitrogen. In certain embodiments,X^(B2) is CR^(B2a), wherein R^(B2a) is as defined herein.

In certain embodiments, X^(B3) is oxygen. In certain embodiments, X^(B3)is sulfur. In certain embodiments, X^(B3) is NR^(B4a), NR^(B4a) is asdefined herein. In certain embodiments, X^(B3) is NH. In certainembodiments, X^(B3) is C(R^(B4b))₂, wherein R^(B4b) is defined herein.

In certain embodiments, X^(B4) is oxygen. In certain embodiments, X^(B4)is sulfur. In certain embodiments, X^(B4) is NR^(B4a), wherein NR^(B4a)is as defined herein. In certain embodiments, X^(B4) is NH. In certainembodiments, X^(B4) is C(R^(B4b))₂, wherein R^(B4b) is defined herein.

In certain embodiments, X^(B1) is NH, and X^(B2) is nitrogen.

In certain embodiments, one or more R^(B1) is independently selectedfrom the group consisting of halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl. Incertain embodiments, one or more R^(B1) is independently halogen. Incertain embodiments, one or more R^(B1) is independently C₁₋₆ alkyl.

In certain embodiments, R^(B2) is hydrogen. In certain embodiments,R^(B2) is halogen.

In certain embodiments, R^(B2) is fluorine. In certain embodiments,R^(B2) is chlorine. In certain embodiments, R^(B2) is bromine. Incertain embodiments, R^(B2) is iodine. In certain embodiments, R^(B2) isC₁₋₆ alkyl. In certain embodiments, R^(B2) is methyl. In certainembodiments, R^(B2) is ethyl. In certain embodiments, R^(B2) is propyl.In certain embodiments, R^(B2) is butyl.

In certain embodiments, R^(B3) is hydrogen. In certain embodiments,R^(B3) is halogen. In certain embodiments, R^(B3) is fluorine. Incertain embodiments, R^(B3) is chlorine. In certain embodiments, R^(B3)is bromine. In certain embodiments, R^(B3) is iodine. In certainembodiments, R^(B3) is C₁₋₆ alkyl. In certain embodiments, R^(B3) ismethyl. In certain embodiments, R^(B3) is ethyl. In certain embodiments,R^(B3) is propyl. In certain embodiments, R^(B3) is butyl.

In certain embodiments, R^(B4) is hydrogen. In certain embodiments,R^(B4) is halogen. In certain embodiments, R^(B4) is fluorine. Incertain embodiments, R^(B4) is chlorine. In certain embodiments, R^(B4)is bromine. In certain embodiments, R^(B4) is iodine. In certainembodiments, R^(B4) is C₁₋₆ alkyl. In certain embodiments, R^(B4) ismethyl. In certain embodiments, R^(B4) is ethyl. In certain embodiments,R^(B4) is propyl. In certain embodiments, R^(B4) is butyl.

In certain embodiments, R^(B5) is hydrogen. In certain embodiments,R^(B5) is halogen. In certain embodiments, R^(B5) is fluorine. Incertain embodiments, R^(B5) is chlorine. In certain embodiments, R^(B5)is bromine. In certain embodiments, R^(B5) is iodine. In certainembodiments, R^(B5) is C₁₋₆ alkyl. In certain embodiments, R^(B5) ismethyl. In certain embodiments, R^(B5) is ethyl. In certain embodiments,R^(B5) is propyl. In certain embodiments, R^(B5) is butyl.

In certain embodiments, R^(B6) is hydrogen. In certain embodiments,R^(B6) is optionally substituted alkyl. In certain embodiments, R^(B6)is optionally substituted C₁₋₆ alkyl. In certain embodiments, R^(B6) ismethyl. In certain embodiments, R^(B6) is ethyl. In certain embodiments,R^(B6) is propyl. In certain embodiments, R^(B6) is butyl. In certainembodiments, R^(B6) is pentyl. In certain embodiments, R^(B6) is hexyl.

In certain embodiments, p is 0. In certain embodiments, p is 1. Incertain embodiments, p is 2. In certain embodiments, p is 3. In certainembodiments, p is 4.

In certain embodiments of Formula (B), wherein p is 1, provided is acompound of any one of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(B1), X^(B2), X^(B3), X^(B4), R^(B1),R^(B2), R^(B3), R^(B4), R^(B5), and R^(B6) are as defined herein.

In certain embodiments, provided is a compound of Formula (B-II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(B3), X^(B4), R^(B2), R^(B3), R^(B4),R^(B5), and R^(B6) are as defined herein.

In certain embodiments, provided is a compound of Formula (B-III):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(B4), R^(B2), R^(B3), R^(B4), R^(B5),and R^(B6) are as defined herein.

In certain embodiments, provided is a compound of Formula (B-IV):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(B3), R^(B2), R^(B3), R^(B4), R^(B5),and R^(B6) are as defined herein.

In certain embodiments, provided is a compound of Formula (B-V):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(B2), R^(B3), R^(B4), R^(B5), and R^(B6)are as defined herein.

In certain embodiments, provided is a compound of Formula (B-VI):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(B4), R^(B5), and R^(B6) are as definedherein.

In certain embodiments, provided is a compound of Formula (B-VII):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(B6) is as defined herein.

In certain embodiments, provided is a compound of Formula (B-VIII):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(B3), X^(B4), R^(B2), R^(B3), R^(B4),and R^(B5) are as defined herein.

In certain embodiments, provided is a compound of Formula (B-IX):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(B1), X^(B2), X^(B3), R^(B1), R^(B4),and R^(B5) are as defined herein.

In a certain embodiment, the compound of Formula (B) is not of theformula:

or a pharmaceutically acceptable salt thereof.

Another hit from the library was identified with a structural frameworkas shown in Formula (C):

Therefore, in certain embodiments, provided is a compound of Formula(C), and pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, and prodrugs thereof, wherein

X^(C1) is oxygen, sulfur, or NR^(C1a), wherein R^(C1a) is hydrogen, anitrogen protecting group, or C₁₋₆ alkyl;

each instance of X^(C2), X^(C3), and X^(C4) is independently nitrogen orCR^(C4a), wherein R^(C4a) is hydrogen, halogen, or C₁₋₆ alkyl;

L is a bond; cyclic or acyclic, substituted or unsubstituted alkylene;cyclic or acyclic, substituted or unsubstituted alkenylene; cyclic oracyclic, substituted or unsubstituted alkynylene; cyclic or acyclic,substituted or unsubstituted heteroalkylene; cyclic or acyclic,substituted or unsubstituted heteroalkenylene; cyclic or acyclic,substituted or unsubstituted heteroalkynylene; substituted orunsubstituted arylene; or substituted or unsubstitutedheteroarylenelene;

each instance of R^(C1) and R^(C2) is independently selected from thegroup consisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(C2a),—N(R^(C2b))₂, —SR^(C2a), —C(═O)R^(C3a), —C(═O)OR^(C2a), —C(═O)SR^(C2a),—C(═O)N(R^(C2b))₂, —OC(═O)R^(C2a), —OC(═O)OR^(C2a), —OC(═O)SR^(C2a),—OC(═O)N(R^(C2b))₂, —NR^(C2b)C(═O)R^(C2b), —NR^(C2b)C(═O) OR^(C2a),—NR^(C2b)C(═O)SR^(C2a), —NR^(C2b)C(═O)N(R^(C2b))₂, —SC(═O)R^(C2a),—SC(═O)OR^(C2a), —SC(═O)SR^(C2a), —SC(═O)N(R^(C2b))₂,—C(═NR^(C2b))R^(C2a), —C(═NR^(C2b))OR^(C2a), —C(═NR^(C2b))SR^(C2a),—C(═NR^(C2b))N(R^(C2b))₂, —OC(═NR^(C2b))R^(C2a), —OC(═NR^(C2b))OR^(C2a),—OC(═NR^(C2b))SR^(C2a), —OC(═NR^(C2b))N(R^(C2b))₂,—NR^(C2b)C(═NR^(C2b))R^(C2b), —NR^(C2b)C(═NR^(C2b))OR^(C2a),—NR^(C2b)C(═NR^(C2b))SR^(C2a), —NR^(C2b)C(═NR^(C2b))N(R^(C2b))₂,—SC(═NR^(C2b))R^(C2a), —SC(═NR^(C2b))OR^(C2a), —SC(═NR^(C2b))SR^(C2a),—SC(═NR^(C2b))N(R^(C2b))₂, —C(═S)R^(C2a), —C(═S)OR^(C2a),—C(═S)SR^(C2a), —C(═S)N(R^(C2b))₂, —OC(═S)R^(C2a), —OC(═S)OR^(C2a),—OC(═S)SR^(C2a), —OC(═S)N(R^(C2b))₂, —NR^(C2b)C(═S)R^(C2b),—NR^(C2b)C(αS)OR^(C2a), —NR^(C2b)C(═S)SR^(C2a),—NR^(C2b)C(═S)N(R^(C2b))₂, —SC(═S)R^(C2a), —SC(═S)OR^(C2a),—SC(═S)SR^(C2a), —SC(═S)N(R^(C2b))₂, —S(═O)R^(C2a), —SO₂R^(C2a),—NR^(C2b)SO₂R^(C2a), —SO₂N(R^(C2b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(C2a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(C2b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(C2b)groups are joined to form an optionally substituted heterocyclic ring;

q is 0, 1, 2, 3, or 4;

r is 0, 1, 2, 3, 4, or 5, and

In certain embodiments, X^(C1) is NR^(C1a) wherein R^(C1a) is hydrogen,a nitrogen protecting group, or C₁₋₆ alkyl. In certain embodiments,X^(C1) is NH. In certain embodiments, X^(C1) is oxygen. In certainembodiments, X^(C1) is sulfur.

In certain embodiments, X^(C2) is nitrogen. In certain embodiments,X^(C2) is CR^(C4a). In certain embodiments, X^(C3) is nitrogen. Incertain embodiments, X^(C3) is CR^(C4a). In certain embodiments, X^(C4)is nitrogen. In certain embodiments, X^(C4) is CR^(C4a). In any of theabove described embodiments, each instance of R^(C4a) is independentlynitrogen or CR^(C4a), wherein R^(C4a) is hydrogen, halogen, or C₁₋₆alkyl.

In certain embodiments, L is a bond. In certain embodiments, L is cyclicor acyclic, substituted or unsubstituted alkylene. In certainembodiments, L is cyclic or acyclic, substituted or unsubstitutedalkenylene. In certain embodiments, L is cyclic or acyclic, substitutedor unsubstituted alkynylene. In certain embodiments, L is cyclic oracyclic, substituted or unsubstituted heteroalkylene. In certainembodiments, L is cyclic or acyclic, substituted or unsubstitutedheteroalkenylene. In certain embodiments, L is cyclic or acyclic,substituted or unsubstituted heteroalkynylene. In certain embodiments, Lis substituted or unsubstituted arylene. In certain embodiments, L issubstituted or unsubstituted heteroarylene.

In certain embodiments, wherein L is substituted or unsubstitutedheteroalkenylene, L comprises at least 5 atoms which are not hydrogen.In certain embodiments, wherein L is substituted or unsubstitutedheteroalkenylene, L comprises at least 4 atoms which are not hydrogen.In certain embodiments, wherein L is substituted or unsubstitutedheteroalkenylene, L comprises at least 3 atoms which are not hydrogen.In certain embodiments, wherein L is substituted or unsubstitutedheteroalkenylene, L comprises at least 2 atoms which are not hydrogen.

In certain embodiments, each instance of R^(C1) is independentlyselected from the group consisting of halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl. Incertain embodiments, at least one R^(C1) is C₁₋₆ alkyl. In certainembodiments, at least one R^(C1) is methyl. In certain embodiments, atleast one R^(C1) is ethyl. In certain embodiments, at least one R^(C1)is propyl. In certain embodiments, at least one R^(C1) is butyl.

In certain embodiments, q is 0. In certain embodiments, q is 1. Incertain embodiments, q is 2. In certain embodiments, q is 3. In certainembodiments, q is 4.

In certain embodiments, r is 0. In certain embodiments, r is 1. Incertain embodiments, r is 2. In certain embodiments, r is 3. In certainembodiments, r is 4. In certain embodiments, r is 5.

In certain embodiments, X^(C1), X^(C2), X^(C3), and X^(C4) are nitrogen.

In certain embodiments, provided is a compound of Formula (C-I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein)

X^(C1), X^(C2), X^(C3), X^(C4), R^(C1), R^(C2), q, and r are as definedherein;

X^(C5) is oxygen, sulfur, NR^(C5a), or C(R^(C5b))₂, wherein R^(C5a) ishydrogen or C₁₋₆ alkyl, and each occurrence of R^(C5b) is hydrogen,halogen, or C₁₋₆ alkyl, or two R^(C5b) groups are joined to form anoptionally substituted carbocyclic or heterocyclic ring; and

each instance of X^(C6) and X^(C7) is independently nitrogen orCR^(C7a), wherein R^(C7a) is hydrogen, halogen, or C₁₋₆ alkyl.

In certain embodiments of Formula (C-I), or a pharmaceuticallyacceptable salt thereof, X^(C5) is NH. In certain embodiments of Formula(C-I), or a pharmaceutically acceptable salt thereof, X^(C5) isNR^(C5a), wherein R^(C5a) is as defined herein.

In certain embodiments of Formula (C-I), or a pharmaceuticallyacceptable salt thereof, X^(C6) is nitrogen.

In certain embodiments of Formula (C-I), or a pharmaceuticallyacceptable salt thereof, X^(C7) is CH. In certain embodiments of Formula(C-I), or a pharmaceutically acceptable salt thereof, X^(C7) isC(R^(C5b))₂, wherein R^(C5b) is as defined herein.

In certain embodiments of Formula (C-I), provided is a compound ofFormula (C-II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X^(C1), X^(C2), X^(C3), X^(C4), R^(C1),R^(C2), q and r are as defined herein.

In certain embodiments, provided is a compound of Formula (C-III):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(C1), R^(C2), q, and r are as definedherein.

In certain embodiments of Formula (C-III), wherein q is 1, provided is acompound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(C1), R^(C2), and r are as definedherein.

In certain embodiments of the formulae (C-III-a), (C-III-b), (C-III-c),and (C-III-d), or a pharmaceutically acceptable salt thereof, whereinR^(C2) and r are as defined herein, R^(C1) is C₁₋₆ alkyl. In certainembodiments of the formulae (C-III-a), (C-III-b), (C-III-c), and(C-III-d), or a pharmaceutically acceptable salt thereof, wherein R^(C2)and r are as defined herein, R^(C1) is methyl. In certain embodiments ofthe formulae (C-III-a), (C-III-b), (C-III-c), and (C-III-d), or apharmaceutically acceptable salt thereof, wherein R^(C2) and r are asdefined herein, R^(C1) is ethyl. In certain embodiments of the formulae(C-III-a), (C-III-b), (C-III-c), and (C-III-d), or a pharmaceuticallyacceptable salt thereof, wherein R^(C2) and r are as defined herein,R^(C1) propyl. In certain embodiments of the formulae (C-III-a),(C-III-b), (C-III-c), and (C-III-d), or a pharmaceutically acceptablesalt thereof, wherein R^(C2) and r are as defined herein, R^(C1) isbutyl.

In certain embodiments, provided is a compound of Formula (C-IV):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(C2) and r are as defined herein.

In certain embodiments, provided is a compound of Formula (C-V):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein each instance of R^(C3) and R^(C4) isindependently selected from the group consisting of halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(C4a), —N(R^(C4b))₂, —SR^(C4a),—C(═O)R^(C4a), —C(═O)OR^(C4a), —C(═O)SR^(C4a), —C(═O)N(R^(C4b))₂,—OC(═O)R^(C4a), —OC(═O)OR^(C4a), —OC(═O)SR^(C4a), —OC(═O)N(R^(C4b))₂,—NR^(C4b)C(═O)R^(C4b), —NR^(C4b)C(═O)OR^(C4a), —NR^(C4b)C(═O)SR^(C4a),—NR^(C4b)C(═O)N(R^(C4b))₂, —SC(═O)R^(C4a), —SC(═O)OR^(C4a),—SC(═O)SR^(C4a), —SC(═O)N(R^(C4b))₂, —C(═NR^(C4b))R^(C4a),—C(═NR^(C4b))OR^(C4a), —C(═NR^(C4b))SR^(C4a), —C(═NR^(C4b))N(R^(C4b))₂,—OC(═NR^(C4b))R^(C4a), —OC(═NR^(C4b))OR^(C4a), —OC(═NR^(C4b))SR^(C4a),—OC(═NR^(C4b))N(R^(C4b))₂, —NR^(C4b)C(═NR^(C4b))R^(C4b),—NR^(C4b)C(═NR^(C4b))OR^(C4a), —NR^(C4b)C(═NR^(C4b))SR^(C4a),—NR^(C4b)C(═NR^(C4b))N(R^(C4b))₂, —SC(═NR^(C4b))R^(C4a),—SC(═NR^(C4b))OR^(C4a), —SC(═NR^(C4b))SR^(C4a),—SC(═NR^(C4b))N(R^(C4b))₂, —C(═S)R^(C4a), —C(═S)OR^(C4a),—C(═S)SR^(C4a), —C(═S)N(R^(C4b))₂, —OC(═S)R^(C4a), —OC(═S)OR^(C4a),—OC(═S)SR^(C4a), —OC(═S)N(R^(C4b))₂, —NR^(C4b)C(═S)R^(C4b),—NR^(C4b)C(═S)OR^(C4a), —NR^(C4b)C(═S)SR^(C4a),—NR^(C4b)C(═S)N(R^(C4b))₂, —SC(═S)R^(C4a), —SC(═S)OR^(C4a),—SC(═S)SR^(C4a), —SC(═S)N(R^(C4b))², —S(═O)R^(C4a), —SO₂R^(C4a),—NR^(C4b)SO₂R^(C4a), —SO₂N(R^(C4b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(C4a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(C4b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(C4b)groups are joined to form an optionally substituted heterocyclic ring;and

v is 0, 1, 2, or 3.

In certain embodiments, v is 0. In certain embodiments, v is 1. Incertain embodiments, v is 2. In certain embodiments, v is 3.

In certain embodiments of Formula (C-V), wherein v is 1, provided is acompound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(C1), R^(C2), R^(C3), R^(C4), and q areas defined herein.

In certain embodiments of the formulae (C-V-a), (C-V-b), and (C-V-c), ora pharmaceutically acceptable salt thereof, R^(C2), R^(C3), or R^(C4) ishydroxyl, —OR^(C2a), —N(R^(C2b))₂, or —SR^(C2a), wherein R^(C1), q,R^(C2a), and R^(C2b) are as defined herein. In certain embodiments ofthe formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceuticallyacceptable salt thereof, R^(C2) and R^(C3) are independently hydroxyl,—OR^(C2a), —N(R^(C2b))₂, or —SR^(C2a), wherein R^(C1), R^(C4), q,R^(C2a), and R^(C2b) are as defined herein. In certain embodiments ofthe formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceuticallyacceptable salt thereof, R^(C2) and R^(C4) are independently hydroxyl,—OR^(C2a), —N(R^(C2b))₂, or —SR^(C2a), wherein R^(C1), R^(C3), q,R^(C2a), and R^(C2b) are as defined herein. In certain embodiments ofthe formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceuticallyacceptable salt thereof, R^(C3) and R^(C4) are independently hydroxyl,—OR^(C2a), —N(R^(C2b))₂, or —SR^(C2a), wherein R^(C1), R^(C2), q,R^(C2a), and R^(C2b) are as defined herein. In certain embodiments ofthe formulae (C-V-a), (C-V-b), and (C-V-c), or a pharmaceuticallyacceptable salt thereof, R^(C2), R^(C3), and R^(C4) are independentlyhydroxyl, —OR^(C2a), —N(R^(C2b))₂, or —SR^(C2a), wherein R^(C1), q,R^(C2a), and R^(C2b) are as defined herein.

In certain embodiments of Formula (C-V), provided is a compound ofFormula (C-VI):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(C1), R^(C3), R^(C4), and q are asdefined herein.

In certain embodiments of Formula (C-VI), or a pharmaceuticallyacceptable salt thereof, R^(C3) is hydroxyl, —OR^(C4a), —N(R^(C4b))₂, or—SR^(C4a), wherein R^(C1), R^(C4), q, R^(C4b), and R^(C4b) are asdefined herein. In certain embodiments of Formula (C-VI), or apharmaceutically acceptable salt thereof, R^(C4) is hydroxyl, —OR^(C4a),—N(R^(C4b))₂, or —SR^(C4a), wherein R^(C1), R^(C3), q, R^(C4a), andR^(C4b) are as defined herein. In certain embodiments of Formula (C-VI),or a pharmaceutically acceptable salt thereof, R^(C3) and R^(C4) areindependently hydroxyl, —OR^(C4a), —N(R^(C4b))₂, or —SR^(C4a), whereinR^(C1), q, R^(C4a), and R^(C4b) are as defined herein. In certainembodiments of Formula (C-VI), R^(C3) and R^(C4) are both hydroxyl,—OR^(C4a), —N(R^(C4b))₂, or —SR^(C4a), wherein R^(C1), q, R^(C4a), andR^(C4b) are as defined herein.

In certain embodiments of Formula (C-V), provided is a compound ofFormula (C-VII):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(C1), R^(C2), q, and v are as definedherein.

In certain embodiments of Formula (C-V), provided is a compound ofFormula (C-VIII):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(C1) and q are as defined herein.

In certain embodiments of Formula (C-VIII), or a pharmaceuticallyacceptable salt thereof, each instance of R^(C1) is C₁₋₆ alkyl. Incertain embodiments of Formula (C-VIII), or a pharmaceuticallyacceptable salt thereof, each instance of R^(C1) is methyl. In certainembodiments of Formula (C-VIII), or a pharmaceutically acceptable saltthereof, each instance of R^(C1) is ethyl. In certain embodiments ofFormula (C-VIII), or a pharmaceutically acceptable salt thereof, eachinstance of R^(C1) is propyl. In certain embodiments of Formula(C-VIII), or a pharmaceutically acceptable salt thereof, each instanceof R^(C1) is butyl.

In certain embodiments of Formula (C-VIII), wherein q is 1, provided isa compound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(C1) is as defined herein.

In certain embodiments, the compound of Formula (C) is not of theformula:

or a pharmaceutically acceptable salt thereof.

Another hit from the library was identified with a structural frameworkas shown in Formula (D):

Therefore, in certain embodiments, provided is a compound of Formula(D), and pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, and prodrugs thereof, wherein each instance of X^(D1) isindependently oxygen, sulfur, NR^(D1a), or C(R^(D1b))₂, wherein R^(D1a)is hydrogen or C₁₋₆ alkyl, and each occurrence of R^(D1b) is hydrogen,halogen, or C₁₋₆ alkyl, or two R^(D1b) groups are joined to form anoptionally substituted carbocyclic or heterocyclic ring;

s is 0, 1, 2, 3, 4, 5, or 6;

each instance of R^(D1) and R^(D2) is independently hydrogen, an oxygenprotecting group, C₁₋₆ alkyl, —C(═O)R^(D2a), —C(═O)OR^(D2a),—C(═O)SR^(D2a), —C(═O)N(R^(D2b))₂, —S(═O)R^(D2a), or —S(═O)₂R^(D2a),wherein each occurrence of R^(D2a) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl, and each occurrence of R^(D2b) is independentlyhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, or a nitrogen protecting group, ortwo R^(D2b) groups are joined to form an optionally substitutedheterocyclic ring;

each instance of R^(D3) and R^(D4) is independently selected from thegroup consisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —)R^(D4a),—N(R^(D4b))₂, —SR^(D4a), —C(═O)R^(D4a), —C(═O)OR^(D4a), —C(═O)SR^(D4a),—C(═O)N(R^(D4b))₂, —OC(═O)R^(D4a), —OC(═O)OR^(D4a), —OC(═O)SR^(D4a),—OC(═O)N(R^(D4b))₂, —NR^(D4b)C(═O)R^(D4b), —NR^(D4b)C(═O)OR^(D4a),—NR^(D4b)C(═O)SR^(D4a), —NR^(D4b)C(═O)N(R^(D4b))₂, —SC(═O)R^(D4a),—SC(═O)OR^(D4a), —SC(═O)SR^(D4a), —SC(═O)N(R^(D4b))₂,—C(═NR^(D4b))R^(D4a), —C(═NR^(D4b))OR^(D4a), —C(═NR^(D4b))SR^(D4)a,—C(═NR^(D4b))N(R^(D4b))₂, —OC(═NR^(D4b))R^(D4a), —OC(═NR^(D4b))OR^(D4a),—OC(═NR^(D4b))SR^(D4a), —OC(═NR^(D4b))N(R^(D4b))₂,—NR^(D4b)C(═NR^(D4b))R^(D4b), —NR^(D4b)C(═NR^(D4b))OR^(D4a),—NR^(D4b)C(═NR^(D4b))SR^(D4a), —NR^(D4b)C(═NR^(D4b))N(R^(D4b))₂,—SC(═NR^(D4b))R^(D4a), —SC(═NR^(D4b))OR^(D4a), —SC(═NR^(D4b))SR^(D4a),—SC(═NR^(D4b))N(R^(D4b))₂, —C(═S)R^(D4a), —C(═S)OR^(D4a),—C(═S)SR^(D4a), —C(═S)N(R^(D4b))₂, —OC(═S)R^(D4a), —OC(═S)OR^(D4a),—OC(═S)SR^(D4a), —OC(═S)N(R^(D4b))₂, —NR^(D4b)C(═S)R^(D4b),—NR^(D4b)C(═S)OR^(D4a), —NR^(D4b)C(═S)SR^(D4a),—NR^(D4b)C(═S)N(R^(D4b))₂, —SC(═S)R^(D4a), —SC(═S)OR^(D4a),—SC(═S)SR^(D4a), —SC(═S)N(R^(D4b))₂, —S(═O)R^(D4a), —SO₂R^(D4a),—NR^(D4b)SO₂R^(D4a), —SO₂N(R^(D4b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(D4a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(D4b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(D4b)groups are joined to form an optionally substituted heterocyclic ring;

t is 0, 1, 2, or 3; and

u is 0, 1, 2, 3, 4 or 5.

In certain embodiments, s is 0. In certain embodiments, s is 1. Incertain embodiments, s is 2. In certain embodiments, s is 3. In certainembodiments, s is 4. In certain embodiments, s is 5. In certainembodiments, s is 6.

In certain embodiments of Formula (D), wherein s is 2, provided is acompound of Formula (D-I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D1), R^(D2), R^(D3), R^(D4), R^(D1a),t, and u are as defined herein.

In certain embodiments of Formula (D-I), provided is a compound ofFormula (D-II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D1), R^(D2), R^(D3), R^(D4), t, and uare as defined herein.

In certain embodiments of Formula (D-II), or a pharmaceuticallyacceptable salt thereof, R^(D1), R^(D2), or both is C₁₋₆ alkyl. Incertain embodiments of Formula (D-II), or a pharmaceutically acceptablesalt thereof, R^(D1), R^(D2), or both is methyl. In certain embodimentsof Formula (D-II), or a pharmaceutically acceptable salt thereof,R^(D1), R^(D2), or both is ethyl. In certain embodiments of Formula(D-II), or a pharmaceutically acceptable salt thereof, R^(D1), R^(D2),or both is propyl. In certain embodiments of Formula (D-II), or apharmaceutically acceptable salt thereof, R^(D1), R^(D2), or both isbutyl.

In certain embodiments of Formula (D-II), wherein t is 1, provided is acompound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D1), R^(D2), R^(D3), R^(D4), and u areas defined herein.

In certain embodiments of Formula (D-II), provided is a compound ofFormula (D-III):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D3), R^(D4), t, and u are as definedherein.

In certain embodiments of Formula (D-III), wherein t is 1, provided is acompound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D3), R^(D4), and u are as definedherein.

In certain embodiments of Formula (D), provided is a compound of Formula(D-III):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein

R^(D1), R^(D2), R^(D3), R^(D4), and t are used as defined herein;

each instance of R^(D5) and R^(D6) is independently selected from thegroup consisting of halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(D6a),—N(R^(D6b))₂, —SR^(D6a), —C(═O)R^(D6a), —C(═O)OR^(D6a), —C(═O)_(SR)^(D6a), —C(═O)N(R^(D6b))₂, —OC(═O)R^(D6a), —OC(═O)OR^(D6a),—OC(═O)SR^(D6a), —OC(═O)N(R^(D6b))₂, —NR^(D6b)C(═O)R^(D6b),—NR^(D6b)C(═O)OR^(D6a), —NR^(D6b)C(═O)SR^(D6a),—NR^(D6b)C(═O)N(R^(D6b))₂, —SC(═O)R^(D6a), —SC(═O)OR^(D6a),—SC(═O)SR^(D6a), —SC(═O)N(R^(D6b))₂, —C(═NR^(D6b))R^(D6a),—C(═NR^(D6b))OR^(D6a), —C(═NR^(D6b))SR^(D6a), —C(═NR^(D6b))N(R^(D6b))₂,—OC(═NR^(D6b))R^(D6a), —OC(═NR^(D6b))OR^(D6a), —OC(═NR^(D6b))SR^(D6a),—OC(═NR^(D6b))N(R^(D6b))₂, —NR^(D6b)C(═NR^(D6b))N(R^(D6b)),—NR^(D6b)C(═NR^(D6b))OR^(D6a), —NR^(D6b)C(═NR^(D6b))SR^(D6a),—NR^(D6b)C(═NR^(D6b))R^(D6b), —NR^(D6b)C(═NR^(D6b))OR^(D6a),—NR^(D6b)C(═NR^(D6b))SR^(D6a), —SC(═NR^(D6b))N(R^(D6b))₂, —C(═S)R^(D6b),—C(═S)OR^(D6a), —C(═S)SR^(D6a), —SC(═NR^(D6b))SR^(D6a), —OC(═S)R^(D6a),—OC(═S)OR^(D6a), —OC(═S)SR^(D6a), —OC(═S)N(R^(D6b))₂,—NR^(D6b)C(═S)R^(D6b), —NR^(D6a)C(═S)OR^(D6a), —NR^(D6b)C(═S)SR^(D6a),—NR^(D6b)C(═S)N(R^(D6b))₂, —SC(═S)R^(D6a), —SC(═S)OR^(D6a),—SC(═S)SR^(D6a), —SC(═S)N(R^(D6b))₂, —S(═O)R^(D6a), —SO₂R^(D6a),—NR^(D6b)SO₂R^(D6a), —SO₂N(R^(D6b))₂, —CN, —SCN, and —NO₂, wherein eachoccurrence of R^(D6a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(D6b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(D6b)groups are joined to form an optionally substituted heterocyclic ring;and

w is 0, 1, 2, or 3.

In certain embodiments of Formula (D-IV), wherein w is 1, provided is acompound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D1), R^(D2), R^(D3), R^(D4), R^(D5),R^(D6), and t are as defined herein.

In certain embodiments of Formula (D-IV), or a pharmaceuticallyacceptable salt thereof, R^(D4), R^(D6), or both are C₁₋₆ alkyl. Incertain embodiments of Formula (D-IV), or a pharmaceutically acceptablesalt thereof, R^(D5), R^(D6), or both are methyl. In certain embodimentsof Formula (D-IV), or a pharmaceutically acceptable salt thereof,R^(D5), R^(D6), or both are ethyl. In certain embodiments of Formula(D-IV), or a pharmaceutically acceptable salt thereof, R^(D5), R^(D6),or both are propyl. In certain embodiments of Formula (D-IV), or apharmaceutically acceptable salt thereof, R^(D5), R^(D6), or both arebutyl.

In certain embodiments, provided is a compound of Formula (D-V):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D1), R^(D2), R^(D3), R^(D4), t and ware as defined herein.

In certain embodiments of Formula (D-V), and pharmaceutically acceptablesalts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, isotopically labeled derivatives, and prodrugs thereof,wherein w is 1, provided is a compound of any of the formulae:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D1), R^(D2), R^(D3), R^(D4), and t areas defined herein.

In certain embodiments, provided is a compound of Formula (D-VI):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R^(D3), R^(D4), t, and w are as definedherein.

In certain embodiments, the compound of Formula (D) is not of theformula:

or a pharmaceutically acceptable salt thereof.Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprising acompound of the present invention, e.g., a compound of any one of theFormulae (A), (B), (C), and (D), and pharmaceutically acceptable salts,solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled derivatives, and prodrugs thereof, as describedherein, and a pharmaceutically acceptable excipient. In certainembodiments, the compound of the present invention or a pharmaceuticallyacceptable salt thereof is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the effective amountis a therapeutically effective amount. In certain embodiments, theeffective amount is a prophylactically effective amount.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of the presentinvention (the “active ingredient”) into association with a carrierand/or one or more other accessory ingredients, and then, if necessaryand/or desirable, shaping and/or packaging the product into a desiredsingle or multidose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is a discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinylpyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20),polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate(Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate(Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitanmonooleate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylenemonostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,polyethoxylated castor oil, polyoxymethylene stearate, and Solutol),sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.Cremophor™), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether(Brij 30)), poly(vinylpyrrolidone), diethylene glycol monolaurate,triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68,Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride,benzalkonium chloride, docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an antioxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor™,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable nonirritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active ingredient can be in microencapsulated form with one or moreexcipients as noted above. The solid dosage forms of tablets, dragees,capsules, pills, and granules can be prepared with coatings and shellssuch as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier and/or any needed preservativesand/or buffers as can be required. Additionally, the present inventioncontemplates the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body. Such dosage forms can be prepared, for example, by dissolvingand/or dispensing the active ingredient in the proper medium.Alternatively or additionally, the rate can be controlled by eitherproviding a rate controlling membrane and/or by dispersing the activeingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid nonionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition of theinvention. Another formulation suitable for intranasal administration isa coarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) and as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition of the invention can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1/1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier. Such drops may furthercomprise buffering agents, salts, and/or one or more other of theadditional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are contemplated asbeing within the scope of this invention.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease, disorder, or conditionbeing treated and the severity of the disorder; the activity of thespecific active ingredient employed; the specific composition employed;the age, body weight, general health, sex and diet of the subject; thetime of administration, route of administration, and rate of excretionof the specific active ingredient employed; the duration of thetreatment; drugs used in combination or coincidental with the specificactive ingredient employed; and like factors well known in the medicalarts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds of the invention may be at dosagelevels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg,from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kgto about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg,from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compounds or compositions can beadministered in combination with additional therapeutically activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body. It will also be appreciated that the therapy employedmay achieve a desired effect for the same disorder, and/or it mayachieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. In will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the inventive compound with the additional therapeutically activeagent and/or the desired therapeutic effect to be achieved. In general,it is expected that additional therapeutically active agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually.

Exemplary additional therapeutically active agents include, but are notlimited to, anti-cancer agents, anti-diabetic agents, anti-inflammatoryagents, immunosuppressant agents, and a pain-relieving agent.Therapeutically active agents include small organic molecules such asdrug compounds (e.g., compounds approved by the U.S. Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins, and cells.

Also encompassed by the invention are kits (e.g., pharmaceutical packs).The kits provided may comprise an inventive pharmaceutical compositionor compound and a container (e.g., a vial, ampule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of an inventive pharmaceutical composition or compound. Insome embodiments, the inventive pharmaceutical composition or compoundprovided in the container and the second container are combined to formone unit dosage form.

Thus, in one aspect, provided is a pharmaceutical composition comprisinga compound of any one of the Formulae (A), (B), (C), and (D), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, and a pharmaceutically acceptable excipient. Incertain embodiments, provided is a composition described herein, whereinthe compound or pharmaceutically acceptable salt thereof is provided inan effective amount.

In another aspect, provided is a kit for treating or preventing aneurological disorder comprising:

a first container comprising an HDAC (histone deacetylase) activator;and instructions for administering the HDAC activator to a subject totreat a neurological disorder. In certain embodiments, the HDACactivator is a class I HDAC activator. In certain embodiments, the classI HDAC activator is an HDAC1 (histone deacetylase 1) activator.

In certain embodiments, provided is a kit for treating a neurologicaldisorder comprising:

a first container comprising the compound of Formula (DAC-001):

and

instructions for administering the compound of Formula (DAC-001) to asubject to treat a neurological disorder.

In certain embodiments, provided is a kit for treating a neurologicaldisorder comprising:

a first container comprising the compound of Formula (DAC-002):

and

instructions for administering the compound of Formula (DAC-002) to asubject to treat a neurological disorder.

In certain embodiments, provided is a kit for treating a neurologicaldisorder comprising:

a first container comprising the compound of Formula (DAC-009):

or a pharmaceutically acceptable salt thereof; and

instructions for administering the compound of Formula (DAC-009) to asubject to treat a neurological disorder.

In certain embodiments, provided is a kit for treating a neurologicaldisorder comprising:

a first container comprising the compound of Formula (DAC-003):

or a pharmaceutically acceptable salt thereof; and

instructions for administering the compound of Formula (DAC-003) to asubject to treat a neurological disorder.

In certain embodiments, provided is a kit for treating a neurologicaldisorder comprising:

a first container comprising the compound of Formula (DAC-012):

or a pharmaceutically acceptable salt thereof; and

instructions for administering the compound of Formula (DAC-012) to asubject to treat a neurological disorder.

In certain embodiments, provided is a kit for treating a neurologicaldisorder comprising:

a first container comprising a compound selected from the group ofcompounds consisting of the compounds of the Formulae (A), (B), (C), and(D), or a pharmaceutically acceptable salt thereof; and

instructions for administering the compound selected in the previousstep to a subject to treat a neurological disorder.

Methods of Treatment

In one aspect, the invention provides methods and compositions for thetreatment or prevention of neurological disorders. In some embodiments,neurological disorders are treated by decreasing the amount of DNAdamage within the neuronal cell. In some embodiments, neurologicaldisorders are treated by increasing HDAC activity within the neuronalcell. In some embodiments, neurological disorders are treated bydecreasing histone acetyl transferase activity within the neuronal cell.In some embodiments, neurological disorders are treated by increasingthe activity of class I histone deacetylases. In some embodiments,neurological disorders are treated by increasing the activity of class IHDAC. In some embodiments, neurological disorders are treated byincreasing the activity of HDAC1. In some embodiments, neurologicaldisorders are treated by increasing the activity of HDAC2. In someembodiments, neurological disorders are treated by increasing theactivity of HDAC3. In some embodiments, neurological disorders aretreated by increasing the activity of HDAC8.

Regulating histone acetylation is an integral aspect of chromatinmodulation and gene regulation that plays a critical role in manybiological processes including cell proliferation and differentiation(Roth et al., Annu. Rev. Biochem. (2001) 70:81-120). Recent reports havedetailed the importance of histone acetylation in CNS functions such asneuronal differentiation, memory formation, drug addiction, anddepression (Citrome, Psychopharmacol. Bull. (2003) 37 Suppl. 2:74-88;Johannessen et al., CNS Drug Rev. (2003) 9:199-216; Tsankova et al.,Nature Neuroscience (2006) 9:519-525). Histone deacetylases removeacetyl groups from histones, resulting in increased chromatin compactionand decreased accessibility to DNA for interacting molecules such astranscription factors (Cerna et al., Curr. Top. Dev. Biol. (2006)73:173-204).

Of the HDACs, HDAC1 was the first protein identified to havehistone-directed deacetylase activity (Taunton et al., Science (1996)272:408-411; Vidal et al., Mol. Cell Biol. (1991) 11:6317-6327). HDAC1plays important roles in regulating the cell cycle and is required inthe transcriptional repression of cell cycle genes such as p21/WAF,E2F-1, and cyclins A and E (Brehm et al., Nature (1998) 391:597-601;Iavarone et al., Mol. Cell Biol. (1999) 19:916-922; Lagger et al., Embo.J. (2002) 21:2672-2681; Rayman et al., Genes Dev. (2002) 16:933-947;Stadler et al., Dev. Dyn. (2005) 233:883-889; Stiegler et al., CancerRes. (1998) 58:5049-5052). The association of HDAC1 with promotorregions of specific genes is linked to their transcriptional repression(Brehm et al., Nature (1998) 391:597-601; Gui et al., Proc. Natl. Acad.Sci. USA (2004) 101:1241-1246; Iavarone et al., Mol. Cell Biol. (1999)19:916-922; Rayman et al., Genes Dev. (2002) 16:933-947).

It has been found that agents that increase HDAC1 activity areneuroprotective (PCT Patent Application Publication No. WO 2010/011318).Those agents may serve for the treatment of neurological disorders,including Alzheimer's disease, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis (ALS), ischemic brain damage,traumatic brain injury, stroke, frontal temporal dementia, Pick'sdisease, corticobasal degeneration, supra cerebral palsy, prion diseases(e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinkersyndrome, Fatal Familial Insomnia, and Kuru), Nieman Pick type C, spinalcerebellar ataxia, spinal muscular dystrophy, ataxia telangiectasia,hippocampal sclerosis, Cockayne syndrome, Werner syndrome, xerodermapigmentosaum, and Bloom syndrome.

Nucleosomes, the primary scaffold of chromatin folding, are dynamicmacromolecular structures, influencing chromatin solution conformations.The nucleosome core is made up of histone proteins, H2A, H2B, H3, andH4. Histone acetylation causes nucleosomes and nucleosomal arrangementsto behave with altered biophysical properties. The balance betweenactivities of histone acetyl transferases (HAT) and histone deacetylasesdetermines the level of histone acetylation. Acetylated histones causerelaxation of chromatin and activation of gene transcription, whereasdeacetylated chromatin generally is transcriptionally inactive.

In some embodiments, neurological disorders are treated by decreasinghistone acetylation by the administration of histone acetylaseactivators. In some embodiments, neurological disorders are treated bydecreasing histone acetylation by methods other than increasing HDACactivity. Methods for decreasing histone acetylation, by a method otherthan a classic HDAC activator include, but are not limited to, theadministration of nucleic acid molecule inhibitors such as antisense andRNAi molecules which reduce the expression of histone acetyltransferases and the administration of histone acetyl transferaseinhibitors. Histone acetyl transferase inhibitors are known in the art(Eliseeva et al., Mol. Cancer Ther. (2007) 6:2391-98). The inventionembraces methods that regulate the function of any protein involved withhistone modification, function and regulation.

In some embodiments, neurological disorders are treated by protectingcells from DNA damage by increasing the histone deacetylation activitywithin the cell. Protection from DNA damage includes both a decrease inthe current level of DNA damage accumulated within the cell, or adecrease in the rate of DNA damage acquired by the cell, including DNAdamage acquired during exposure of the cell to DNA damaging events, suchas exposure to DNA damaging agents, including radiation, and events thatlead to increased oxidative stress. Increased deacetylase activity canprotect against any form of DNA damage, including base modifications,DNA single strand breaks, and DNA double strand breaks. DNA doublestrand breaks are potentially the most damaging to the cell, and otherforms of DNA damage can be turned into DNA double strand breaks by theaction of DNA repair enzymes and other cellular processes. DNA damage,including DNA double strand breaks, can accumulate in both activelydividing and non-dividing cells. In actively dividing cells, DNA doublestrand breaks may inhibit the replication machinery, while in bothactively dividing and non-dividing cells the transcription machinery maybe inhibited by DNA double strand breaks. In addition, DNA double strandbreaks may initiate potentially damaging recombination events. Thus,increased deacetylase activity may be protective in any cell type,including dividing and non-dividing cells. In some embodiments,increased deacetylase activity is protective in neuronal cells. In someembodiments, increased deacetylase activity is induced in cells that aresusceptible to acquiring DNA damage, or cells that will be subjected toa DNA damage inducing event. For instance, histone deacetylase activitymay be increased in cells or tissue in a subject that need to beprotected when a DNA damaging agent is administered throughout the body(for instance, during chemotherapy). In some embodiments,neuroprotection is provided by increasing the histone deacetylationactivity within a neuronal cell. In some embodiments, neuroprotection isprovided by decreasing the histone acetyl transferase activity within aneuronal cell.

The invention embraces any method of increasing deacetylase activity. Insome embodiments, deacetylase activity is increased by increasing theactivity of class I HDAC. In some embodiments, deacetylase activity isincreased by increasing the activity of HDAC1. In some embodiments,deacetylase activity is increased by increasing the activity of HDAC2.In some embodiments, deacetylase activity is increased by increasing theactivity of HDAC3. In some embodiments, deacetylase activity isincreased by increasing the activity of HDAC8. In some embodiments,deacetylase activity is increased by adding an HDAC activator to thecell. In some embodiments, the HDAC activator is a class I HDACactivator. In some embodiments, the HDAC activator is an HDAC1activator. In some embodiments, the HDAC activator is an HDAC2activator. In some embodiments, the HDAC activator is an HDAC3activator. In some embodiments, the HDAC activator is an HDAC8activator. In some embodiments, HDAC activity is increased by increasingthe expression level of one or more HDACs. In some embodiments, HDACactivity is increased by selectively increasing the expression level ofone or more HDACs relative to one or more HDACs. In some embodiments,HDAC activity is increased by selectively increasing the expressionlevel of one or more HDACs by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% to 60%, 60%to 70%, 70% to 80%, 80% to 90%, or 90% to 100% relative to one or moreHDACs. In some embodiments, HDAC activity is increased by selectivelyincreasing the expression level of one or more HDACs by 100% to 200%,200% to 300%, 300% to 500%, 500% to 1000%, 1000% to 10000%, or 10000% to100000% relative to one or more other HDACs. In some embodiments, theexpression level is increased by increasing the level and/or activity oftranscription factors that act on a specific gene encoding a histonedeacetylase. In some embodiments, the activity is increased bydecreasing the activity of repressor elements. In some embodiments,deacetylase activity within a cell or subject is increased byadministering histone deacetylase protein to the cell or subject. Insome embodiments, the activity is increased by inactivating orsequestering an agent that acts as an inhibitor on a HDAC suppressorpathway.

An “HDAC activator” as defined herein is any compound that results in anincrease in the level of HDAC activity. Any increase in enzymaticfunction of an HDAC is embraced by the invention. In some embodiments,the activity increase of HDAC is an increase in HDAC deacetylaseactivity. In some embodiments, the activity increase of HDAC is anincrease in HDAC esterase activity. HDAC activity corresponds to thelevel of histone deacetylase activity of the HDAC. One of ordinary skillin the art can select suitable compounds on the basis of the knownstructures of histone deacetylases. Examples of such compounds arepeptides, nucleic acids expressing such peptides, small molecules, etc.,each of which can be naturally occurring molecules, synthetic molecules,and/or FDA approved molecules, that specifically react with the histonedeacetylase and increase its activity.

In certain embodiments, the HDAC activator is a naturally occurringcompound or a compound that has been synthesized, or a pharmaceuticallyacceptable salt thereof, such as a compound of the Formula (DAC-001),(DAC-002), (DAC-003), (DAC-009), or (DAC-012), or pharmaceuticallyacceptable salt thereof.

In certain embodiments, the HDAC activator is a compound of Formula (A),(B), (C), or (D), or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of the compound of Formula(DAC-001), or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of the compound of Formula(DAC-002), or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of the compound of Formula(DAC-009), or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of the compound of Formula(DAC-003), or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of the compound of Formula(DAC-012), or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of a compound of Formula(A), or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of a compound of Formula(B), or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of a compound of Formula(C), or a pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a method for treating or preventinga neurological disorder in a subject, the method comprisingadministering to a subject in need of treatment for a neurologicaldisorder a therapeutically effective amount of a compound of Formula(D), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the neurological disorder being treated orprevented is Alzheimer's disease.

In certain embodiments, the neurological disorder being treated orprevented is Parkinson's disease.

In certain embodiments, the neurological disorder being treated orprevented is Huntington's disease.

In certain embodiments, the neurological disorder being treated orprevented is ALS (amyotrophic lateral sclerosis).

In certain embodiments, the neurological disorder being treated orprevented is traumatic brain injury.

In certain embodiments, the neurological disorder being treated orprevented is ischemic brain injury.

In certain embodiments, the neurological disorder being treated orprevented is stroke.

In certain embodiments, the neurological disorder being treated orprevented is frontal temporal dementia.

In certain embodiments, the neurological disorder being treated orprevented is Pick's disease.

In certain embodiments, the neurological disorder being treated orprevented is corticobasal degeneration.

In certain embodiments, the neurological disorder being treated orprevented is supra cerebral palsy.

In certain embodiments, the neurological disorder being treated orprevented is prion diseases (e.g., Creutzfeldt-Jakob disease,Gerstmann-Straussler-Scheinker syndrome, Fatal Familial Insomnia, andKuru).

In certain embodiments, the neurological disorder being treated orprevented is Nieman Pick type C.

In certain embodiments, the neurological disorder being treated orprevented is spinal cerebellar ataxia.

In certain embodiments, the neurological disorder being treated orprevented is spinal muscular dystrophy.

In certain embodiments, the neurological disorder being treated orprevented is ataxia telangiectasia.

In certain embodiments, the neurological disorder being treated orprevented is hippocampal sclerosis.

In certain embodiments, the neurological disorder being treated orprevented is Cockayne syndrome.

In certain embodiments, the neurological disorder being treated orprevented is Werner syndrome.

In certain embodiments, the neurological disorder being treated orprevented is xeroderma pigmentosaum.

In certain embodiments, the neurological disorder being treated orprevented is Bloom syndrome.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

Example 1. Recombinant HDAC1 Expression, Purification, and ProteomicAnalysis

Recombinant, full-length human HDAC1 (GenBank Accession No. NM_004964)with a C-terminal FLAG tag was produced by BPS Biosciences (San Diego,Calif.) using large-scale insect cell protein expression andpurification in order to support a large-scale high-throughput screen(HTS).

To determine the quality of the protein preparation, and to confirm theexistence of only HDAC1 as the only deacetylase in the preparation,NanoLC-MS/MS peptide sequencing technology was carried out by ProtTech,Inc (Norristown, Pa.). In brief, each protein gel band was destained,cleaned, and digested in-gel with sequencing grade modified trypsinobtained from Promega (Madison, Wis.). All other chemicals used inproteolytic digestion and HPLC were obtained from Sigma (St. Louis,Mo.). The resulting peptide mixture was analyzed using a LC-MS/MS systemThermo (Palo Alto, Calif.), in which a high pressure liquidchromatography (HPLC) with a 75 micrometer inner diameter reverse phaseC₁₈ column was on-line coupled with a Quadrupole ion trap massspectrometer. The mass spectrometric data acquired were used to searchthe most recent non-redundant protein database (downloaded from NCBI)with ProtTech's proprietary software suite.

For the two principle bands in the preparation isolated after SDS-PAGE,the first was identified as histone deacetylase 1 (HDAC1) with multiplepeptides with a minor fraction of peptides from chaperonin TCP-1β4 thatcontains t-complex polypeptide 1 (TCP-1) beta subunit 4 (β4) from theSf9 cells. The second predominant band was identified as heat shockcognate protein 70 (HSC70) from the Sf9 cells with a minor fraction ofHDAC1. Interestingly, HSC70 has been reported to have ATPase function,which is common to many chromatin-remodeling complexes, and HSC70 hasbeen shown to interact with Tau protein, a protein implicated in thepathology of Alzheimer's disease and other neurodegenerative disorders.An “ATPase” is an enzyme that uses ATP, i.e., adenosine triphosphate, asan energy source. In the case of TCP-1β4, these findings are ofpotential interest because, for HDAC3, a similar class I HDAC, theassembly of the SMRT-HDAC3 co-repressor complex requires the TCP-1 ringcomplex (Guenther et al., Genes Dev. (2002) 16:3130-35). It is thuspossible that the regulation of HDAC1 conformation by TCP-1 ring complexis important for its deacetylase activity, which will be taken intoconsideration when the mechanisms of action of hits identified in theHTS are analyzed.

Example 2. Primary HDAC1 High-Throughput Screen

Using the microfluidics-based HDAC1 assay developed by Nanosyn (Durham,N.C.) at total of 47,144 compounds from a diverse, drug-like librarywere tested for their ability to enhance the deacetylase activity ofrecombinant HDAC1. Compounds were tested with a reaction time of 6 hwith compounds tested at a single concentration (10 μM) in duplicate. Asa positive control, the biflavonoid gingketin was chosen.

High-Throughput Screen Information

47,144 compounds were tested for their effect on the enzymatic activityof HDAC1. Compounds were tested in duplicate at 10 μM nominal finalconcentration in 384-well plate format. The reference activatorcompound, ginkgetin (50 μM), was included in duplicates in each HTSplate as a positive control condition. 24 negative control samples (DMSOonly) were included in each plate to provide for the 0% activationbaseline.

Screening Results

Within each HTS plate, the effect of individual compounds on theenzymatic activity of HDAC1 was calculated as % change in the conversionof the peptide substrate relative to the average substrate conversionvalue calculated across the 24 negative control samples.

A compounds was considered active if its effect (calculated as averageof two duplicates) on the enzymatic activity of HDAC1 is above the 66standard deviations value of the assay, which is the commonly acceptedstatistical significance threshold for active compounds in HTS.

HDAC1 microfluidics assay control data of 7,080 negative control samples(DMSO) and 580 ginkgetin positive control samples (50 μM) are shown inFIG. 2A and FIG. 2B, respectively.

FIGS. 3A to 3B include HDAC1 HTS data. FIG. 3A depicts a primarymicrofluidic fluorescence reader trace for ginkgetin (positive control)showing increased conversion of the peptidic substrate FAM-TSRHKacKL tothe deacetylated product FAM-TSRHKKL (illustrated with arrows). FIG. 3Bdepicts a primary microfluidic fluorescence reader trace for DAC-001,showing increased conversion of the peptidic substrate FAM-TSRHKacKL tothe deacetylated product FAM-TSRHKKL (illustrated with arrows).

HTS results are summarized in Table 1. A total of 21 hits, includingDAC-001, DAC-002, DAC-003, DAC-009, and DAC-012, were identified by theHTS, the structures of which were determined using HPLC/UV/MS/ELSDanalysis. Analysis of the structures of the hit compounds revealedmultiple common structural frameworks suggesting the existence of adefined structure-activity-relationship for HDAC1 activation. Allconfirmed hits were re-ordered from commercial sources for furthertesting. Percent activation data are included in Table 2 for ginkgetin,DAC-001, DAC-002, DAC-003, DAC-009, and DAC-012.

TABLE 1 Summary of data obtained from high-thoughput screening Totalnumber of compounds screened 47,144 6σ value of the assay 15.5%activation Positive Name ginkgetin control Total number of measurements580 Average effect 26% activation (standard deviation: 4%) Measurementsabove 6σ 571 (98.5% of total number of measurements) Measurements below6σ 9 (1.5% of total number of measurements) Estimated probability that apotentially active <0.00023 compound has not been detected in at leastone of the two replica samples Total number of active compounds 21(0.044% of total number of compounds screened)

TABLE 2 Activation of HDAC1 by certain compounds in high-thoughputscreening Percent activation (%) Compound ID Replicate 1 Replicate 2Average ginkgetin 25.6 ± 4.7 DAC-001 122.6 138.4 130.5 DAC-002 52.7 56.654.7 DAC-003 24.2 24.9 24.6 DAC-009 15.1 22.2 18.7 DAC-012 17.5 17.917.7

Example 3. Secondary HDAC1 High-Throughput Screen

Based upon the results of the HDAC1 activator screen performed, a totalof 21 compounds (for structures, see FIGS. 6A to 6C) were initiallyselected as hits due to their ability to enhance the deacetylaseactivity of recombinant HDAC1. Those hits, designated as “DACs”(deacetylase activating compounds), were measured using amicrofluidics-based assay with an acetylated peptidic substrate(FAM-TSRHKacKL) over a reaction time of 6 h. The 21 HTS hits plus twocontrols: ginkgetin (an activator) and TSA (trichostatin A, aninhibitor; for its structure, see FIG. 6A) were retested in an 8-pointdose response ranging from 50 μM to 0.02 μM. The positive control(ginkgetin) again demonstrated dose-dependent activation of HDAC1(maximal effect of 20% and plateau at 10 μM), HDAC2 (AC₅₀═28 μM, maximaleffect 165%) and HDAC3 (maximal effect 20% at 100 μM). TSA demonstrateddose dependent inhibition of all HDAC isoforms as expected. Compoundswere considered as confirmed hits if their AC₅₀ curve showeddose-dependent activation of the HDAC1 activity in microfluidics-basedassay. The two most active HTS hits, compounds DAC-001 and DAC-002demonstrated activation of up to 287% and 221% with AC₅₀ values of 4.05μM and 8.31 μM, respectively. These data, included in Table 3,demonstrate the successful discovery of compounds that activate thedeacetylase activity of HDAC1 in vitro.

TABLE 3 Activation of HDAC1 by certain comopunds in amicrofluidics-based assay with an acetylated peptidic substrate(FAM-TSRHKacKL) Average activation Maximum activation % during % duringHTS dose response (50 μM Compound ID (10 μM) maximum) Ginkgetin 25.6 23Trichostatin A 0 0 DAC-001 130.5 287 DAC-002 54.7 221 DAC-003 24.6 34DAC-009 18.7 12 DAC-012 17.7 26

Microfluidics-based deacetylase assays were also performed usingrecombinant HDAC2, HDAC3, and HDAC8 to determine the selectivity of thecompounds. Many of the confirmed compounds also activated HDAC2 isoformto a similar or even greater extent. Some compounds activated HDAC3 andinhibited the HDAC8 isoform.

Example 4. Characterization of HDAC1 Activators in Cellular Models ofNeurodegeneration

Next, what was tested was whether a treatment of HDAC1 activators canincrease HDAC1 enzymatic activity in cultured cells. Human HEK293T cellswere treated with compounds at different concentrations (10 μM or 50 μM)for 20 h. Histone proteins were extracted, and Western blotting was usedto analyze the acetylation of certain histone lysine residues known tobe HDAC1 targets. Treatment with some compounds, such as DAC-001,DAC-002, DAC-003, and DAC-009, reduced the levels of Ac-H3K56, Ac-H3K14,Ac-H4K12 and Ac-H2B, indicating those compounds' ability to activateHDAC1 in cultured cells (FIG. 4).

HT-22 cells, a hippocampal neuron derived cell line, were used to modelneurodegeneration. Two types of insults were used. Glutamate treatmentinduced oxidative stress by depleting glutathione. Etoposide, atopoisomerase II inhibitor, stressed cells through DNA damage. These twotypes of stresses have been documented in neurodegenerative diseases.

HT-22 cells were treated with compounds for 3 h prior to the addition of2.5 mM glutamate. Cell viability was measured by CellTiter-Glo assays(Promega) (FIG. 5A). DAC-003 can significantly protect cells fromoxidative stress (p<0.05, student's t-test). DAC-012 also showed a trendof protection.

Similarly, HT-22 cells were pre-incubated with compounds (5 μM forDAC-001 and DAC-003; 10 μM for others) for 3 h. Then, 2 μM etoposide wasadded to the culture medium. Cell viability was measured 72 h later(FIG. 5B). Of the DAC compounds tested, DAC-001, DAC-002, DAC-003,DAC-009, and DAC-012 showed significant protection (p<0.001, student'st-test) against DNA damage stress. This result is consistent withprevious findings that HDAC1 is directly involved in DNA damage repair,and that over-expression of HDAC1 is able to protect neurons from DNAdamage.

Additionally, the safety of these compounds was tested in HT-22 cells(FIG. 5C). Cell survival was measured 72 h after compound treatment.Most compounds showed minimum effects (less than 10%) upon cellsurvival. This data also indicate that DAC compounds are less likely toaffect cell proliferation.

The neuroprotection potential of the candidate compounds were alsotested using a neuronal excitoxicity model. DIV14 cortical neurons weretreated with the compounds for 20 h. 50 μM glutamate was added to theculture 1 h before processing the samples for immunocytochemistry. MAP2staining for the neuronal dendrites demonstrated that treatment withsome of the compounds was able to protect neurons from excitotoxicity,as evidenced by their retention of dendrites. Ginkgetin was used as apositive control. Of the DAC compounds tested, DAC-002 and DAC-003showed a trend of protection, while DAC-001 showed significantprotection (p<0.01, student's t-test).

What is claimed is:
 1. A compound of Formula (B):

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof, wherein: each of X^(B1), X^(B3), and X^(B4) isindependently oxygen, sulfur, NR^(B4a), or C(R^(B4b))₂, wherein R^(B4a)is hydrogen, a nitrogen protecting group, or optionally substituted C₁₋₆alkyl, and each occurrence of R^(B4b) is independently hydrogen,halogen, or optionally substituted C₁₋₆ alkyl, or two R^(B4b) groups arejoined to form an optionally substituted, carbocyclic or heterocyclicring; X^(B2) is nitrogen or CR^(B2a), wherein R^(B2a) is hydrogen,halogen, or optionally substituted C₁₋₆ alkyl; each instance of R^(B1)is independently halogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(B1a),—N(R^(B1a))₂, —SR^(B1a), —C(═O)R^(B1a), —C(═O)OR^(B1a), —C(═O)SR^(B1a),—C(═O)N(R^(B1b))₂, —OC(═O)R^(B1a), OC(═O)OR^(B1a), —OC(═O)SR^(B1a),—OC(═O)N(R^(B1b))₂, —NR^(B1b)C(═O)R^(B1b), —NR^(B1b)C(═O)OR^(B1a),—NR^(B1b)C(═O)SR^(B1a), —NR^(B1b)C(═O)N(R^(B1b))₂, —SC(═O)R^(B1a),—SC(═O)OR^(B1a), —SC(═O)SR^(B1a)SC(═O)N(R^(B1b))₂, —C(═NR^(B1b))R^(B1a),—C(═NR^(B1b))OR^(B1a), —C(═NR^(B1b))SR^(B1a), —C(═NR^(B1b))N(R^(B1b))₂,—OC(═NR^(Bb))R^(B1a), —OC(═NR^(B1b))OR^(B1a), —OC(═NR^(B1b))SR^(B1a),—OC(═NR^(B1b))N(R^(B1b))₂, —NR^(B1b)C(═NR^(B1b))R^(B1b),—NR^(B1b)C(═NR^(B1b))OR^(B1a), —NR^(B1b)C(═NR^(B1b))SR^(B1a),NR^(B1b)C(═NR^(B1b))N(R^(B1b))₂, —SC(═NR^(B1b))R^(B1a),—SC(═NR^(B1b))OR^(B1a), —SC(═NR^(B1b))SR^(B1a) SC(═NR^(B1b))N(R^(B1b))₂,—C(═S)R^(B1a), —C(═S)OR^(B1a), —C(═S)SR^(B1a), —C(═S)N(R^(B1b))₂,—OC(═S)R^(B1a), OC(═S)OR^(B1a), —OC(═S)SR^(B1a), —OC(═S)N(R^(B1b))₂,—NR^(B1b)C(═S)R^(B1b), —NR^(B1b)C(═S)OR^(B1a), —NR^(B1b)C(═S)SR^(B1a),—NR^(B1b)C(═S)N(R^(B1b))₂, —SC(═S)R^(B1a), —SC(═S)OR^(B1a),—SC(═S)SR^(B1a), SC(═S)N(R^(B1b))₂, —S(═O)R^(B1a), —SO₂R^(B1a),—NR^(B1b)SO₂R^(B1a), —SO₂N(R^(B1b))₂, —CN, —SCN, or —NO₂, wherein eachoccurrence of R^(B1a) is independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(B1b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group when attached toa nitrogen atom, or two R^(B1b) groups are joined to form an optionallysubstituted heterocyclic ring; each of R^(B2), R^(B3), R^(B4), andR^(B5) is independently hydrogen, halogen, or optionally substitutedC₁₋₆ alkyl; R^(B6) is hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —N(R^(B6b))₂, or—SR^(B6a), wherein R^(B6a) is hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, andeach occurrence of R^(B6b) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group, or two R^(B6b)groups are joined to form an optionally substituted heterocyclic ring;and p is 0, 1, 2, 3, or 4; provided that the compound is not of theformula:


2. The compound of claim 1, or a pharmaceutically acceptable salt,tautomer, stereoisomer, or prodrug thereof, wherein X^(B1) is NH, andX^(B2) is nitrogen.
 3. The compound of claim 2, wherein the compound isof formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt, tautomer, stereoisomer, or prodrug thereof, whereinX^(B3) is sulfur.
 5. The compound of claim 1, wherein the compound is offormula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt, tautomer, stereoisomer, or prodrug thereof, whereinX^(B4) is oxygen.
 7. The compound of claim 1, wherein the compound is offormula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 8. The compound of claim 7, wherein the compound is offormula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt, tautomer, stereoisomer, or prodrug thereof, whereinR^(B2) and R^(B3) are hydrogen.
 10. The compound of claim 9, or apharmaceutically acceptable salt, tautomer, stereoisomer, or prodrugthereof, wherein R^(B4) and R^(B5) are optionally substituted C₁₋₆alkyl.
 11. The compound of claim 1, wherein the compound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 12. The compound of claim 1, wherein the compound is offormula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 13. The compound of claim 1, wherein the compound is offormula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 14. The compound of claim 1, or a pharmaceuticallyacceptable salt, tautomer, stereoisomer, or prodrug thereof, whereinR^(B6) is unsubstituted ethyl.
 15. The compound of claim 1, wherein thecompound is of formula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 16. The compound of claim 1, wherein the compound is offormula:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof.
 17. A pharmaceutical composition comprising a compoundof claim 1, or a pharmaceutically acceptable salt, tautomer,stereoisomer, or prodrug thereof, and optionally a pharmaceuticallyacceptable excipient.
 18. A method for therapeutically treating aneurological disorder in a subject, the method comprising administeringto a subject in need of therapeutic treatment for a neurologicaldisorder a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt, tautomer, stereoisomer, or prodrugthereof, wherein the neurological disorder is Alzheimer's disease orfrontal temporal dementia.
 19. The method of claim 18, wherein theneurological disorder is Alzheimer's disease.
 20. The compound of claim1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, orprodrug thereof, wherein p is
 0. 21. The compound of claim 1, or apharmaceutically acceptable salt, tautomer, stereoisomer, or prodrugthereof, wherein R^(B6) is optionally substituted C₁₋₆ alkyl.
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt, tautomer,stereoisomer, or prodrug thereof, wherein R^(B6) is unsubstituted C₁₋₆alkyl.
 23. The method of claim 18, wherein the neurological disorder isfrontal temporal dementia.
 24. The compound of claim 1, or apharmaceutically acceptable salt thereof.
 25. The pharmaceuticalcomposition of claim 17 comprising the compound, or a pharmaceuticallyacceptable salt thereof, and optionally a pharmaceutically acceptableexcipient.
 26. The method of claim 18 comprising administering to asubject in need of therapeutic treatment for Alzheimer's disease atherapeutically effective amount of the compound, or a pharmaceuticallyacceptable salt thereof.
 27. The method of claim 18 comprisingadministering to a subject in need of therapeutic treatment for frontaltemporal dementia a therapeutically effective amount of the compound, ora pharmaceutically acceptable salt thereof.